Clustering O
of O
missense O
mutations O
in O
the O
ataxia B
- I
telangiectasia I
gene O
in O
a O
sporadic O
T I
- I
cell I
leukaemia I
. O

Ataxia B
- I
telangiectasia I
( O
A B
- I
T I
) O
is O
a O
recessive B
multi I
- I
system I
disorder I
caused O
by O
mutations O
in O
the O
ATM O
gene O
at O
11q22 O
- O
q23 O
( O
ref O
. O
3 O
) O
. O

The O
risk O
of O
cancer B
, O
especially O
lymphoid B
neoplasias I
, O
is O
substantially O
elevated O
in O
A B
- I
T I
patients O
and O
has O
long O
been O
associated O
with O
chromosomal O
instability O
. O

By O
analysing O
tumour B
DNA O
from O
patients O
with O
sporadic B
T I
- I
cell I
prolymphocytic I
leukaemia I
( O
T B
- I
PLL I
) O
, O
a O
rare O
clonal B
malignancy I
with O
similarities O
to O
a O
mature O
T I
- I
cell I
leukaemia I
seen O
in O
A B
- I
T I
, O
we O
demonstrate O
a O
high O
frequency O
of O
ATM O
mutations O
in O
T B
- I
PLL I
. O

In O
marked O
contrast O
to O
the O
ATM O
mutation O
pattern O
in O
A B
- I
T I
, O
the O
most O
frequent O
nucleotide O
changes O
in O
this O
leukaemia B
were O
missense O
mutations O
. O

These O
clustered O
in O
the O
region O
corresponding O
to O
the O
kinase O
domain O
, O
which O
is O
highly O
conserved O
in O
ATM O
- O
related O
proteins O
in O
mouse O
, O
yeast O
and O
Drosophila O
. O

The O
resulting O
amino O
- O
acid O
substitutions O
are O
predicted O
to O
interfere O
with O
ATP O
binding O
or O
substrate O
recognition O
. O

Two O
of O
seventeen O
mutated O
T O
- O
PLL O
samples O
had O
a O
previously O
reported O
A B
- I
T I
allele O
. O

In O
contrast O
, O
no O
mutations O
were O
detected O
in O
the O
p53 O
gene O
, O
suggesting O
that O
this O
tumour B
suppressor O
is O
not O
frequently O
altered O
in O
this O
leukaemia B
. O

Occasional O
missense O
mutations O
in O
ATM O
were O
also O
found O
in O
tumour B
DNA O
from O
patients O
with O
B B
- I
cell I
non I
- I
Hodgkins I
lymphomas I
( O
B B
- I
NHL I
) O
and O
a O
B B
- I
NHL I
cell O
line O
. O

The O
evidence O
of O
a O
significant O
proportion O
of O
loss O
- O
of O
- O
function O
mutations O
and O
a O
complete O
absence O
of O
the O
normal O
copy O
of O
ATM O
in O
the O
majority O
of O
mutated O
tumours B
establishes O
somatic O
inactivation O
of O
this O
gene O
in O
the O
pathogenesis O
of O
sporadic O
T B
- I
PLL I
and O
suggests O
that O
ATM O
acts O
as O
a O
tumour B
suppressor O
. O

As O
constitutional O
DNA O
was O
not O
available O
, O
a O
putative O
hereditary O
predisposition O
to O
T B
- I
PLL I
will O
require O
further O
investigation O
. O
. O

Myotonic B
dystrophy I
protein O
kinase O
is O
involved O
in O
the O
modulation O
of O
the O
Ca2 O
+ O
homeostasis O
in O
skeletal O
muscle O
cells O
. O

Myotonic B
dystrophy I
( O
DM B
) O
, O
the O
most O
prevalent O
muscular B
disorder I
in O
adults O
, O
is O
caused O
by O
( O
CTG O
) O
n O
- O
repeat O
expansion O
in O
a O
gene O
encoding O
a O
protein O
kinase O
( O
DM B
protein O
kinase O
; O
DMPK O
) O
and O
involves O
changes O
in O
cytoarchitecture O
and O
ion O
homeostasis O
. O

To O
obtain O
clues O
to O
the O
normal O
biological O
role O
of O
DMPK O
in O
cellular O
ion O
homeostasis O
, O
we O
have O
compared O
the O
resting O
[ O
Ca2 O
+ O
] O
i O
, O
the O
amplitude O
and O
shape O
of O
depolarization O
- O
induced O
Ca2 O
+ O
transients O
, O
and O
the O
content O
of O
ATP O
- O
driven O
ion O
pumps O
in O
cultured O
skeletal O
muscle O
cells O
of O
wild O
- O
type O
and O
DMPK O
[ O
- O
/ O
- O
] O
knockout O
mice O
. O

In O
vitro O
- O
differentiated O
DMPK O
[ O
- O
/ O
- O
] O
myotubes O
exhibit O
a O
higher O
resting O
[ O
Ca2 O
+ O
] O
i O
than O
do O
wild O
- O
type O
myotubes O
because O
of O
an O
altered O
open O
probability O
of O
voltage O
- O
dependent O
l O
- O
type O
Ca2 O
+ O
and O
Na O
+ O
channels O
. O

The O
mutant O
myotubes O
exhibit O
smaller O
and O
slower O
Ca2 O
+ O
responses O
upon O
triggering O
by O
acetylcholine O
or O
high O
external O
K O
+ O
. O

In O
addition O
, O
we O
observed O
that O
these O
Ca2 O
+ O
transients O
partially O
result O
from O
an O
influx O
of O
extracellular O
Ca2 O
+ O
through O
the O
l O
- O
type O
Ca2 O
+ O
channel O
. O

Neither O
the O
content O
nor O
the O
activity O
of O
Na O
+ O
/ O
K O
+ O
ATPase O
and O
sarcoplasmic O
reticulum O
Ca2 O
+ O
- O
ATPase O
are O
affected O
by O
DMPK O
absence O
. O

In O
conclusion O
, O
our O
data O
suggest O
that O
DMPK O
is O
involved O
in O
modulating O
the O
initial O
events O
of O
excitation O
- O
contraction O
coupling O
in O
skeletal O
muscle O
. O
. O

Constitutional O
RB1 O
- O
gene O
mutations O
in O
patients O
with O
isolated B
unilateral I
retinoblastoma I
. O

In O
most O
patients O
with O
isolated B
unilateral I
retinoblastoma I
, O
tumor B
development O
is O
initiated O
by O
somatic O
inactivation O
of O
both O
alleles O
of O
the O
RB1 O
gene O
. O

However O
, O
some O
of O
these O
patients O
can O
transmit O
retinoblastoma B
predisposition O
to O
their O
offspring O
. O

To O
determine O
the O
frequency O
and O
nature O
of O
constitutional O
RB1 O
- O
gene O
mutations O
in O
patients O
with O
isolated B
unilateral I
retinoblastoma I
, O
we O
analyzed O
DNA O
from O
peripheral O
blood O
and O
from O
tumor B
tissue O
. O

The O
analysis O
of O
tumors B
from O
54 O
( O
71 O
% O
) O
of O
76 O
informative O
patients O
showed O
loss O
of O
constitutional O
heterozygosity O
( O
LOH O
) O
at O
intragenic O
loci O
. O

Three O
of O
13 O
uninformative O
patients O
had O
constitutional O
deletions O
. O

For O
39 O
randomly O
selected O
tumors B
, O
SSCP O
, O
hetero O
- O
duplex O
analysis O
, O
sequencing O
, O
and O
Southern O
blot O
analysis O
were O
used O
to O
identify O
mutations O
. O

Mutations O
were O
detected O
in O
21 O
( O
91 O
% O
) O
of O
23 O
tumors B
with O
LOH O
. O

In O
6 O
( O
38 O
% O
) O
of O
16 O
tumors B
without O
LOH O
, O
one O
mutation O
was O
detected O
, O
and O
in O
9 O
( O
56 O
% O
) O
of O
the O
tumors B
without O
LOH O
, O
both O
mutations O
were O
found O
. O

Thus O
, O
a O
total O
of O
45 O
mutations O
were O
identified O
in O
tumors B
of O
36 O
patients O
. O

Thirty O
- O
nine O
of O
the O
mutations O
- O
including O
34 O
small O
mutations O
, O
2 O
large O
structural O
alterations O
, O
and O
hypermethylation O
in O
3 O
tumors B
- O
were O
not O
detected O
in O
the O
corresponding O
peripheral O
blood O
DNA O
. O

In O
6 O
( O
17 O
% O
) O
of O
the O
36 O
patients O
, O
a O
mutation O
was O
detected O
in O
constitutional O
DNA O
, O
and O
1 O
of O
these O
mutations O
is O
known O
to O
be O
associated O
with O
reduced O
expressivity O
. O

The O
presence O
of O
a O
constitutional O
mutation O
was O
not O
associated O
with O
an O
early O
age O
at O
treatment O
. O

In O
1 O
patient O
, O
somatic O
mosaicism O
was O
demonstrated O
by O
molecular O
analysis O
of O
DNA O
and O
RNA O
from O
peripheral O
blood O
. O

In O
2 O
patients O
without O
a O
detectable O
mutation O
in O
peripheral O
blood O
, O
mosaicism O
was O
suggested O
because O
1 O
of O
the O
patients O
showed O
multifocal B
tumors I
and O
the O
other O
later O
developed O
bilateral B
retinoblastoma I
. O

In O
conclusion O
, O
our O
results O
emphasize O
that O
the O
manifestation O
and O
transmissibility O
of O
retinoblastoma B
depend O
on O
the O
nature O
of O
the O
first O
mutation O
, O
its O
time O
in O
development O
, O
and O
the O
number O
and O
types O
of O
cells O
that O
are O
affected O
. O
. O

Hereditary B
deficiency I
of I
the I
fifth I
component I
of I
complement I
in O
man O
. O

I O
. O

Clinical O
, O
immunochemical O
, O
and O
family O
studies O
. O

The O
first O
recognized O
human O
kindred O
with O
hereditary B
deficiency I
of I
the I
fifth I
component I
of I
complement I
( O
C5 O
) O
is O
described O
. O

The O
proband O
, O
a O
20 O
- O
year O
- O
old O
black O
female O
with O
systemic B
lupus I
erythematosus I
since O
age O
11 O
, O
lacked O
serum O
hemolytic O
complement O
activity O
, O
even O
during O
remission O
. O

C5 O
was O
undetectable O
in O
her O
serum O
by O
both O
immunodiffusion O
and O
hemolytic O
assays O
. O

Other O
complement O
components O
were O
normal O
during O
remission O
of O
lupus B
, O
but O
C1 O
, O
C4 O
, O
C2 O
, O
and O
C3 O
levels O
fell O
during O
exacerbations O
. O

A O
younger O
half O
- O
sister O
, O
who O
had O
no O
underlying O
disease O
, O
was O
also O
found O
to O
lack O
immunochemically O
detectable O
C5 O
. O

By O
hemolytic O
assay O
, O
she O
exhibited O
1 O
- O
2 O
% O
of O
the O
normal O
serum O
C5 O
level O
and O
normal O
concentrations O
of O
other O
complement O
components O
. O

C5 O
levels O
of O
other O
family O
members O
were O
either O
normal O
or O
approximately O
half O
- O
normal O
, O
consistent O
with O
autosomal O
codominant O
inheritance O
of O
the O
gene O
determining O
C5 B
deficiency I
. O

Normal O
hemolytic O
titers O
were O
restored O
to O
both O
homozygous O
C5 B
- I
deficient I
( O
C5D O
) O
sera O
by O
addition O
of O
highly O
purified O
human O
C5 O
. O

In O
specific O
C5 O
titrations O
, O
however O
, O
it O
was O
noted O
that O
when O
limited O
amounts O
of O
C5 O
were O
assayed O
in O
the O
presence O
of O
low O
dilutions O
of O
either O
C5D B
serum O
, O
curving O
rather O
than O
linear O
dose O
- O
response O
plots O
were O
consistently O
obtained O
, O
suggesting O
some O
inhibitory O
effect O
. O

Further O
studies O
suggested O
that O
low O
dilutions O
of O
C5D B
serum O
contain O
a O
factor O
( O
or O
factors O
) O
interfering O
at O
some O
step O
in O
the O
hemolytic O
assay O
of O
C5 O
, O
rather O
than O
a O
true O
C5 O
inhibitor O
or O
inactivator O
. O

Of O
clinical O
interest O
are O
( O
a O
) O
the O
documentation O
of O
membranous O
glomerulonephritis B
, O
vasculitis B
, O
and O
arthritis B
in O
an O
individual O
lacking O
C5 O
( O
and O
its O
biologic O
functions O
) O
, O
and O
( O
b O
) O
a O
remarkable O
propensity O
to O
bacterial B
infections I
in O
the O
proband O
, O
even O
during O
periods O
of O
low O
- O
dose O
or O
alternate O
- O
day O
corticosteroid O
therapy O
. O

Other O
observations O
indicate O
that O
the O
C5D O
state O
is O
compatible O
with O
normal O
coagulation O
function O
and O
the O
capacity O
to O
mount O
a O
neutrophilic B
leukocytosis I
during O
pyogenic B
infection I
. O
. O

Susceptibility O
to O
ankylosing B
spondylitis I
in O
twins O
: O
the O
role O
of O
genes O
, O
HLA O
, O
and O
the O
environment O
. O

OBJECTIVE O
To O
determine O
the O
relative O
effects O
of O
genetic O
and O
environmental O
factors O
in O
susceptibility O
to O
ankylosing B
spondylitis I
( O
AS B
) O
. O

METHODS O
Twins O
with O
AS B
were O
identified O
from O
the O
Royal O
National O
Hospital O
for O
Rheumatic B
Diseases I
database O
. O

Clinical O
and O
radiographic O
examinations O
were O
performed O
to O
establish O
diagnoses O
, O
and O
disease O
severity O
was O
assessed O
using O
a O
combination O
of O
validated O
scoring O
systems O
. O

HLA O
typing O
for O
HLA O
- O
B27 O
, O
HLA O
- O
B60 O
, O
and O
HLA O
- O
DR1 O
was O
performed O
by O
polymerase O
chain O
reaction O
with O
sequence O
- O
specific O
primers O
, O
and O
zygosity O
was O
assessed O
using O
microsatellite O
markers O
. O

Genetic O
and O
environmental O
variance O
components O
were O
assessed O
with O
the O
program O
Mx O
, O
using O
data O
from O
this O
and O
previous O
studies O
of O
twins O
with O
AS B
. O

RESULTS O
Six O
of O
8 O
monozygotic O
( O
MZ O
) O
twin O
pairs O
were O
disease O
concordant O
, O
compared O
with O
4 O
of O
15 O
B27 O
- O
positive O
dizygotic O
( O
DZ O
) O
twin O
pairs O
( O
27 O
% O
) O
and O
4 O
of O
32 O
DZ O
twin O
pairs O
overall O
( O
12 O
. O
5 O
% O
) O
. O

Nonsignificant O
increases O
in O
similarity O
with O
regard O
to O
age O
at O
disease O
onset O
and O
all O
of O
the O
disease O
severity O
scores O
assessed O
were O
noted O
in O
disease O
- O
concordant O
MZ O
twins O
compared O
with O
concordant O
DZ O
twins O
. O

HLA O
- O
B27 O
and O
B60 O
were O
associated O
with O
the O
disease O
in O
probands O
, O
and O
the O
rate O
of O
disease O
concordance O
was O
significantly O
increased O
among O
DZ O
twin O
pairs O
in O
which O
the O
co O
- O
twin O
was O
positive O
for O
both O
B27 O
and O
DR1 O
. O

Additive O
genetic O
effects O
were O
estimated O
to O
contribute O
97 O
% O
of O
the O
population O
variance O
. O

CONCLUSION O
Susceptibility O
to O
AS B
is O
largely O
genetically O
determined O
, O
and O
the O
environmental O
trigger O
for O
the O
disease O
is O
probably O
ubiquitous O
. O

HLA O
- O
B27 O
accounts O
for O
a O
minority O
of O
the O
overall O
genetic O
susceptibility O
to O
AS B
. O

Cell O
cycle O
- O
dependent O
colocalization O
of O
BARD1 O
and O
BRCA1 O
proteins O
in O
discrete O
nuclear O
domains O
. O

Germ O
- O
line O
mutations O
of O
the O
BRCA1 O
gene O
predispose O
women O
to O
early O
- O
onset O
breast B
and I
ovarian I
cancer I
by O
compromising O
the O
genes O
presumptive O
function O
as O
a O
tumor B
suppressor O
. O

Although O
the O
biochemical O
properties O
of O
BRCA1 O
polypeptides O
are O
not O
understood O
, O
their O
expression O
pattern O
and O
subcellular O
localization O
suggest O
a O
role O
in O
cell O
- O
cycle O
regulation O
. O

When O
resting O
cells O
are O
induced O
to O
proliferate O
, O
the O
steady O
- O
state O
levels O
of O
BRCA1 O
increase O
in O
late O
G1 O
and O
reach O
a O
maximum O
during O
S O
phase O
. O

Moreover O
, O
in O
S O
phase O
cells O
, O
BRCA1 O
polypeptides O
are O
hyperphosphorylated O
and O
accumulate O
into O
discrete O
subnuclear O
foci O
termed O
" O
BRCA1 O
nuclear O
dots O
. O

" O
BRCA1 O
associates O
in O
vivo O
with O
a O
structurally O
related O
protein O
termed O
BARD1 O
. O

Here O
we O
show O
that O
the O
steady O
- O
state O
levels O
of O
BARD1 O
, O
unlike O
those O
of O
BRCA1 O
, O
remain O
relatively O
constant O
during O
cell O
cycle O
progression O
. O

However O
, O
immunostaining O
revealed O
that O
BARD1 O
resides O
within O
BRCA1 O
nuclear O
dots O
during O
S O
phase O
of O
the O
cell O
cycle O
, O
but O
not O
during O
the O
G1 O
phase O
. O

Nevertheless O
, O
BARD1 O
polypeptides O
are O
found O
exclusively O
in O
the O
nuclear O
fractions O
of O
both O
G1 O
- O
and O
S O
- O
phase O
cells O
. O

Therefore O
, O
progression O
to O
S O
phase O
is O
accompanied O
by O
the O
aggregation O
of O
nuclear O
BARD1 O
polypeptides O
into O
BRCA1 O
nuclear O
dots O
. O

This O
cell O
cycle O
- O
dependent O
colocalization O
of O
BARD1 O
and O
BRCA1 O
indicates O
a O
role O
for O
BARD1 O
in O
BRCA1 O
- O
mediated O
tumor B
suppression O
. O

Ethnic O
differences O
in O
the O
HFE O
codon O
282 O
( O
Cys O
/ O
Tyr O
) O
polymorphism O
. O

Recent O
studies O
have O
shown O
that O
hereditary B
hemochromatosis I
( O
HH B
) O
is O
likely O
to O
be O
caused O
by O
homozygosity O
for O
a O
Cys282Tyr O
mutation O
in O
the O
HFE O
gene O
located O
4 O
. O

5 O
Mb O
telomeric O
to O
HLA O
- O
A O
. O

Population O
studies O
of O
this O
polymorphism O
are O
facilitated O
by O
the O
fact O
that O
the O
Cys282Tyr O
mutation O
creates O
a O
Rsal O
restriction O
site O
. O

We O
have O
studied O
the O
codon O
282 O
( O
Cys O
/ O
Tyr O
) O
polymorphism O
in O
different O
ethnic O
groups O
. O

In O
agreement O
with O
previous O
observations O
the O
Tyr O
allele O
appeared O
to O
be O
rare O
or O
absent O
in O
Asiatic O
( O
Indian O
, O
Chinese O
) O
populations O
. O

The O
highest O
allele O
frequency O
( O
7 O
. O
5 O
% O
) O
was O
found O
in O
Swedes O
. O

Saamis O
( O
2 O
% O
) O
and O
Mordvinians O
( O
1 O
. O
8 O
% O
) O
had O
significantly O
lower O
frequencies O
of O
the O
Tyr O
allele O
. O

Comparisons O
with O
allele O
frequencies O
based O
on O
prevalence O
estimates O
of O
HH B
showed O
some O
disagreements O
with O
the O
RFLP O
data O
, O
particularly O
in O
Finns O
. O

The O
newly O
described O
HFE O
marker O
provides O
a O
new O
approach O
to O
the O
screening O
of O
HH O
as O
well O
as O
studies O
of O
the O
relationship O
between O
the O
HFE O
Tyr O
allele O
and O
different O
disorders O
including O
cancer B

Autosomal B
dominant I
neurohypophyseal I
diabetes I
insipidus I
associated O
with O
a O
missense O
mutation O
encoding O
Gly23 O
- O
- O
> O
Val O
in O
neurophysin O
II O
. O

Autosomal B
dominant I
neurohypophyseal I
diabetes I
insipidus I
( O
ADNDI B
) O
is O
an O
inherited B
disease I
caused O
by O
progressive O
degeneration B
of I
the I
magnocellular I
neurons I
of I
the I
hypothalamus I
leading O
to O
decreased O
ability O
to O
produce O
the O
hormone O
arginine O
vasopressin O
( O
AVP O
) O
. O

Affected O
individuals O
are O
not O
symptomatic O
at O
birth O
, O
but O
usually O
develop O
diabetes B
insipidus I
at O
1 O
- O
6 O
yr O
of O
age O
. O

The O
genetic O
locus O
of O
the O
disease O
is O
the O
AVP O
- O
neurophysin O
II O
( O
NPII O
) O
gene O
, O
and O
mutations O
that O
cause O
ADNDI B
have O
been O
found O
in O
both O
the O
signal O
peptide O
of O
the O
prepro O
- O
AVP O
- O
NPII O
precursor O
and O
within O
NPII O
itself O
. O

An O
affected O
girl O
who O
presented O
at O
9 O
months O
of O
age O
and O
her O
similarly O
affected O
younger O
brother O
and O
father O
were O
all O
found O
to O
have O
a O
novel O
missense O
mutation O
( O
G1758 O
- O
- O
> O
T O
) O
encoding O
the O
amino O
acid O
substitution O
Gly23 O
- O
- O
> O
Val O
within O
NPII O
. O

The O
mutation O
was O
confirmed O
by O
restriction O
endonuclease O
analysis O
. O

A O
T1 O
- O
weighted O
magnetic O
resonance O
imaging O
of O
the O
fathers O
pituitary O
gland O
demonstrates O
an O
attenuated O
posterior O
pituitary O
bright O
spot O
. O

This O
mutation O
may O
be O
valuable O
for O
developing O
models O
of O
dominantly O
inherited O
neurodegeneration I
, O
as O
the O
early O
age O
of O
onset O
of O
symptoms O
suggests O
that O
this O
mutation O
may O
be O
particularly O
deleterious O
to O
the O
magnocellular O
neuron O
. O
. O

Frequent O
inactivation O
of O
PTEN O
/ O
MMAC1 O
in O
primary O
prostate I
cancer I
. O

Sporadic B
prostate I
carcinoma I
is O
the O
most O
common O
male B
cancer I
in O
the O
Western O
world O
, O
yet O
many O
of O
the O
major O
genetic O
events O
involved O
in O
the O
progression O
of O
this O
often O
fatal O
cancer B
remain O
to O
be O
elucidated O
. O

Numerous O
cytogenetic O
and O
allelotype O
studies O
have O
reported O
frequent O
loss O
of O
heterozygosity O
on O
chromosomal O
arm O
10q O
in O
sporadic B
prostate I
cancer I
. O

Deletion O
mapping O
studies O
have O
unambiguously O
identified O
a O
region O
of O
chromosome O
10q23 O
to O
be O
the O
minimal O
area O
of O
loss O
. O

A O
new O
tumor B
suppressor O
gene O
, O
PTEN O
/ O
MMAC1 O
, O
was O
isolated O
recently O
at O
this O
region O
of O
chromosome O
10q23 O
and O
found O
to O
be O
inactivated O
by O
mutation O
in O
three O
prostate B
cancer I
cell O
lines O
. O

We O
screened O
80 O
prostate B
tumors I
by O
microsatellite O
analysis O
and O
found O
chromosome O
10q23 O
to O
be O
deleted O
in O
23 O
cases O
. O

We O
then O
proceeded O
with O
sequence O
analysis O
of O
the O
entire O
PTEN O
/ O
MMAC1 O
coding O
region O
and O
tested O
for O
homozygous O
deletion O
with O
new O
intragenic O
markers O
in O
these O
23 O
cases O
with O
10q23 O
loss O
of O
heterozygosity O
. O

The O
identification O
of O
the O
second O
mutational O
event O
in O
10 O
( O
43 O
% O
) O
tumors B
establishes O
PTEN O
/ O
MMAC1 O
as O
a O
main O
inactivation O
target O
of O
10q O
loss O
in O
sporadic B
prostate I
cancer I
. O
. O

Risk O
reversals O
in O
predictive O
testing O
for O
Huntington B
disease I
. O

The O
first O
predictive O
testing O
for O
Huntington B
disease I
( O
HD B
) O
was O
based O
on O
analysis O
of O
linked O
polymorphic O
DNA O
markers O
to O
estimate O
the O
likelihood O
of O
inheriting O
the O
mutation O
for O
HD B
. O

Limits O
to O
accuracy O
included O
recombination O
between O
the O
DNA O
markers O
and O
the O
mutation O
, O
pedigree O
structure O
, O
and O
whether O
DNA O
samples O
were O
available O
from O
family O
members O
. O

With O
direct O
tests O
for O
the O
HD B
mutation O
, O
we O
have O
assessed O
the O
accuracy O
of O
results O
obtained O
by O
linkage O
approaches O
when O
requested O
to O
do O
so O
by O
the O
test O
individuals O
. O

For O
six O
such O
individuals O
, O
there O
was O
significant O
disparity O
between O
the O
tests O
. O

Three O
went O
from O
a O
decreased O
risk O
to O
an O
increased O
risk O
, O
while O
in O
another O
three O
the O
risk O
was O
decreased O
. O

Knowledge O
of O
the O
potential O
reasons O
for O
these O
changes O
in O
results O
and O
impact O
of O
these O
risk O
reversals O
on O
both O
patients O
and O
the O
counseling O
team O
can O
assist O
in O
the O
development O
of O
strategies O
for O
the O
prevention O
and O
, O
where O
necessary O
, O
management O
of O
a O
risk O
reversal O
in O
any O
predictive O
testing O
program O
. O
. O

A O
novel O
common O
missense O
mutation O
G301C O
in O
the O
N O
- O
acetylgalactosamine O
- O
6 O
- O
sulfate O
sulfatase O
gene O
in O
mucopolysaccharidosis B
IVA I
. O

Mucopolysaccharidosis B
IVA I
( O
MPS B
IVA I
) O
is O
an O
autosomal B
recessive I
lysosomal I
storage I
disorder I
caused O
by O
a O
genetic B
defect I
in I
N I
- I
acetylgalactosamine I
- I
6 I
- I
sulfate I
sulfatase I
( O
GALNS O
) O
. O

In O
previous O
studies O
, O
we O
have O
found O
two O
common O
mutations O
in O
Caucasians O
and O
Japanese O
, O
respectively O
. O

To O
characterize O
the O
mutational O
spectrum O
in O
various O
ethnic O
groups O
, O
mutations O
in O
the O
GALNS O
gene O
in O
Colombian O
MPS B
IVA I
patients O
were O
investigated O
, O
and O
genetic O
backgrounds O
were O
extensively O
analyzed O
to O
identify O
racial O
origin O
, O
based O
on O
mitochondrial O
DNA O
( O
mtDNA O
) O
lineages O
. O

Three O
novel O
missense O
mutations O
never O
identified O
previously O
in O
other O
populations O
and O
found O
in O
16 O
out O
of O
19 O
Colombian O
MPS B
IVA I
unrelated O
alleles O
account O
for O
84 O
. O

2 O
% O
of O
the O
alleles O
in O
this O
study O
. O

The O
G301C O
and O
S162F O
mutations O
account O
for O
68 O
. O

4 O
% O
and O
10 O
. O

5 O
% O
of O
mutations O
, O
respectively O
, O
whereas O
the O
remaining O
F69V O
is O
limited O
to O
a O
single O
allele O
. O

The O
skewed O
prevalence O
of O
G301C O
in O
only O
Colombian O
patients O
and O
haplotype O
analysis O
by O
restriction O
fragment O
length O
polymorphisms O
in O
the O
GALNS O
gene O
suggest O
that O
G301C O
originated O
from O
a O
common O
ancestor O
. O

Investigation O
of O
the O
genetic O
background O
by O
means O
of O
mtDNA O
lineages O
indicate O
that O
all O
our O
patients O
are O
probably O
of O
native O
American O
descent O

Low O
frequency O
of O
BRCA1 O
germline O
mutations O
in O
45 O
German O
breast B
/ I
ovarian I
cancer I
families O
. O

In O
this O
study O
we O
investigated O
45 O
German O
breast B
/ I
ovarian I
cancer I
families O
for O
germline O
mutations O
in O
the O
BRCA1 O
gene O
. O

We O
identified O
four O
germline O
mutations O
in O
three O
breast B
cancer I
families O
and O
in O
one O
breast B
- I
ovarian I
cancer I
family O
. O
among O
these O
were O
one O
frameshift O
mutation O
, O
one O
nonsense O
mutation O
, O
one O
novel O
splice O
site O
mutation O
, O
and O
one O
missense O
mutation O
. O

The O
missense O
mutation O
was O
also O
found O
in O
2 O
. O

8 O
% O
of O
the O
general O
population O
, O
suggesting O
that O
it O
is O
not O
disease O
associated O
. O

The O
average O
age O
of O
disease O
onset O
in O
those O
families O
harbouring O
causative O
mutations O
was O
between O
32 O
. O

3 O
and O
37 O
. O

4 O
years O
, O
whereas O
the O
family O
harbouring O
the O
missense O
mutation O
had O
an O
average O
age O
of O
onset O
of O
51 O
. O

2 O
years O
. O

These O
findings O
show O
that O
BRCA1 O
is O
implicated O
in O
a O
small O
fraction O
of O
breast B
/ I
ovarian I
cancer I
families O
suggesting O
the O
involvement O
of O
another O
susceptibility O
gene O
( O
s O
) O

Paternal O
transmission O
of O
congenital B
myotonic I
dystrophy I
. O

We O
report O
a O
rare O
case O
of O
paternally O
transmitted O
congenital B
myotonic I
dystrophy I
( O
DM B
) O
. O

The O
proband O
is O
a O
23 O
year O
old O
, O
mentally B
retarded I
male O
who O
suffers O
severe O
muscular B
weakness I
. O

He O
presented O
with O
respiratory O
and O
feeding O
difficulties O
at O
birth O
. O

His O
two O
sibs O
suffer O
from O
childhood O
onset O
DM B
. O

Their O
late O
father O
had O
the O
adult O
type O
of O
DM B
, O
with O
onset O
around O
30 O
years O
. O

Only O
six O
other O
cases O
of O
paternal O
transmission O
of O
congenital O
DM B
have O
been O
reported O
recently O
. O

We O
review O
the O
sex O
related O
effects O
on O
transmission O
of O
congenital O
DM B
. O

Decreased O
fertility O
of O
males O
with O
adult O
onset O
DM B
and O
contraction O
of O
the O
repeat O
upon O
male O
transmission O
contribute O
to O
the O
almost O
absent O
occurrence O
of O
paternal O
transmission O
of O
congenital O
DM B
. O

Also O
the O
fathers O
of O
the O
reported O
congenitally O
affected O
children O
showed O
, O
on O
average O
, O
shorter O
CTG O
repeat O
lengths O
and O
hence O
less O
severe O
clinical O
symptoms O
than O
the O
mothers O
of O
children O
with O
congenital O
DM B
. O

We O
conclude O
that O
paternal O
transmission O
of O
congenital O
DM B
is O
rare O
and O
preferentially O
occurs O
with O
onset O
of O
DM B
past O
30 O
years O
in O
the O
father O
. O
. O

The O
RB1 O
gene O
mutation O
in O
a O
child O
with O
ectopic B
intracranial I
retinoblastoma I
. O

The O
RB1 O
gene O
mutation O
was O
investigated O
in O
a O
child O
with O
ectopic B
intracranial I
retinoblastoma I
using O
DNA O
obtained O
from O
both O
the O
pineal B
and I
retinal I
tumours I
of O
the O
patient O
. O

A O
nonsense O
mutation O
in O
exon O
17 O
( O
codon O
556 O
) O
of O
the O
RB1 O
gene O
was O
found O
to O
be O
present O
homozygously O
in O
both O
the O
retinal B
and I
the I
pineal I
tumours I
. O

The O
same O
mutation O
was O
present O
heterozygously O
in O
the O
DNA O
from O
the O
constitutional O
cells O
of O
the O
patient O
, O
proving O
it O
to O
be O
of O
germline O
origin O
. O

The O
initial O
mutation O
was O
shown O
to O
have O
occurred O
in O
the O
paternally O
derived O
RB1 O
allele O
. O

The O
mutation O
is O
in O
an O
area O
of O
the O
gene O
that O
encodes O
the O
protein O
- O
binding O
region O
known O
as O
the O
pocket O
region O
and O
has O
been O
detected O
in O
other O
cases O
of O
retinoblastoma B
. O
. O

Low O
levels O
of O
beta O
hexosaminidase O
A O
in O
healthy O
individuals O
with O
apparent O
deficiency O
of O
this O
enzyme O
. O

Appreciable O
beta O
hexosaminidase O
A O
( O
hex O
A O
) O
activity O
has O
been O
detected O
in O
cultured O
skin O
fibroblasts O
and O
melanoma B
tissue O
from O
healthy O
individuals O
previously O
reported O
as O
having O
deficiency B
of I
hex I
A I
activity O
indistinguishable O
from O
that O
of O
patients O
with O
Tay B
- I
Sachs I
disease I
( O
TSD B
) O
. O

Identification O
and O
quantitation O
of O
hex O
A O
, O
amounting O
to O
3 O
. O

5 O
% O
- O
6 O
. O

9 O
% O
of O
total O
beta O
hexosaminidase O
activity O
, O
has O
been O
obtained O
by O
cellulose O
acetate O
gel O
electrophoresis O
, O
DEAE O
- O
cellulose O
ion O
- O
exchange O
chromatography O
, O
radial O
immunodiffusion O
, O
and O
radioimmunoassay O
. O

Previous O
family O
studies O
suggested O
that O
these O
individuals O
may O
be O
compound O
heterozygotes O
for O
the O
common O
mutant O
TSD B
gene O
and O
a O
rare O
( O
allelic O
) O
mutant O
gene O
. O

Thus O
, O
the O
postulated O
rate O
mutant O
gene O
appears O
to O
code O
for O
the O
expression O
of O
low O
amounts O
of O
hex O
A O
. O

Heterozygotes O
for O
the O
rare O
mutant O
may O
be O
indistinguishable O
from O
heterozygotes O
for O
the O
common O
TSD B
mutant O
. O

However O
, O
direct O
visualization O
and O
quantitation O
of O
hex O
A O
by O
the O
methods O
described O
may O
prevent O
false O
- O
positive O
prenatal O
diagnosis O
of O
TSD B
in O
fetuses O
having O
the O
incomplete O
hex I
A I
deficiency I
of O
the O
type O
described O
in O
the O
four O
healthy O
individuals O

The O
tumor B
suppressor O
gene O
Smad4 O
/ O
Dpc4 O
is O
required O
for O
gastrulation O
and O
later O
for O
anterior O
development O
of O
the O
mouse O
embryo O
. O

Mutations O
in O
the O
SMAD4 O
/ O
DPC4 O
tumor B
suppressor O
gene O
, O
a O
key O
signal O
transducer O
in O
most O
TGFbeta O
- O
related O
pathways O
, O
are O
involved O
in O
50 O
% O
of O
pancreatic B
cancers I
. O

Homozygous O
Smad4 O
mutant O
mice O
die O
before O
day O
7 O
. O

5 O
of O
embryogenesis O
. O

Mutant O
embryos O
have O
reduced O
size O
, O
fail O
to O
gastrulate O
or O
express O
a O
mesodermal O
marker O
, O
and O
show O
abnormal O
visceral O
endoderm O
development O
. O

Growth B
retardation I
of O
the O
Smad4 B
- I
deficient I
embryos O
results O
from O
reduced O
cell O
proliferation O
rather O
than O
increased O
apoptosis O
. O

Aggregation O
of O
mutant O
Smad4 O
ES O
cells O
with O
wild O
- O
type O
tetraploid O
morulae O
rescues O
the O
gastrulation O
defect O
. O

These O
results O
indicate O
that O
Smad4 O
is O
initially O
required O
for O
the O
differentiation O
of O
the O
visceral O
endoderm O
and O
that O
the O
gastrulation O
defect O
in O
the O
epiblast O
is O
secondary O
and O
non O
- O
cell O
autonomous O
. O

Rescued O
embryos O
show O
severe O
anterior O
truncations O
, O
indicating O
a O
second O
important O
role O
for O
Smad4 O
in O
anterior O
patterning O
during O
embryogenesis O
. O

Prevalence O
of O
p16 O
and O
CDK4 O
germline O
mutations O
in O
48 O
melanoma B
- O
prone I
families O
in O
France O
. O

The O
French O
Familial B
Melanoma I
Study O
Group O
. O

Germline O
mutations O
in O
the O
p16 O
and O
CDK4 O
genes O
have O
been O
reported O
in O
a O
subset O
of O
melanoma B
pedigrees O
, O
but O
their O
prevalence O
is O
not O
well O
known O
. O

We O
searched O
for O
such O
germline O
mutations O
in O
48 O
French O
melanoma B
- I
prone I
families O
selected O
according O
to O
two O
major O
criteria O
families O
with O
at O
least O
three O
affected O
members O
( O
n O
= O
20 O
) O
or O
families O
with O
two O
affected O
members O
, O
one O
of O
them O
affected O
before O
the O
age O
of O
50 O
( O
n O
= O
28 O
) O
, O
and O
one O
additional O
minor O
criterion O
. O

Sixteen O
different O
p16 O
germline O
mutations O
were O
found O
in O
21 O
families O
, O
while O
one O
germline O
mutation O
, O
Arg24His O
, O
was O
detected O
in O
the O
CDK4 O
gene O
. O

The O
frequency O
of O
p16 O
gene O
mutation O
in O
our O
sample O
( O
44 O
% O
) O
is O
among O
the O
highest O
rates O
yet O
reported O
and O
the O
CDK4 O
mutation O
is O
the O
second O
mutation O
detected O
in O
this O
gene O
worldwide O
. O

In O
summary O
, O
our O
results O
show O
frequent O
involvement O
of O
the O
p16 O
gene O
in O
familial B
melanoma I
and O
confirm O
the O
role O
of O
the O
CDK4 O
gene O
as O
a O
melanoma B
- O
predisposing O
gene O
. O
. O

Progression O
of O
somatic O
CTG O
repeat O
length O
heterogeneity O
in O
the O
blood O
cells O
of O
myotonic B
dystrophy I
patients O
. O

The O
genetic O
basis O
of O
myotonic B
dystrophy I
( O
DM B
) O
is O
the O
expansion O
of O
an O
unstable O
CTG O
repeat O
in O
the O
34 O
UTR O
of O
the O
DM B
protein O
kinase O
gene O
on O
chromosome O
19 O
. O

One O
of O
the O
principal O
features O
of O
the O
DM B
mutation O
is O
an O
extraordinarily O
high O
level O
of O
somatic O
mosaicism O
, O
due O
to O
an O
extremely O
high O
degree O
of O
somatic O
instability O
both O
within O
and O
between O
different O
tissues O
. O

This O
instability O
appears O
to O
be O
biased O
towards O
further O
expansion O
and O
continuous O
throughout O
the O
life O
of O
an O
individual O
, O
features O
that O
could O
be O
associated O
with O
the O
progressive O
nature O
of O
the O
disease O
. O

Although O
increasing O
measured O
allele O
size O
between O
patients O
clearly O
correlates O
with O
an O
increased O
severity O
of O
symptoms O
and O
an O
earlier O
age O
of O
onset O
, O
this O
correlation O
is O
not O
precise O
and O
measured O
allele O
length O
cannot O
be O
used O
as O
an O
accurate O
predictor O
of O
age O
of O
onset O
. O

In O
order O
to O
further O
characterize O
the O
dynamics O
of O
DM B
CTG O
repeat O
somatic O
instability O
, O
we O
have O
studied O
repeat O
length O
changes O
over O
time O
in O
111 O
myotonic B
dystrophy I
patients O
with O
varying O
clinical O
severity O
and O
CTG O
repeat O
size O
over O
time O
intervals O
of O
1 O
- O
7 O
years O
. O

We O
have O
found O
a O
direct O
progression O
of O
the O
size O
heterogeneity O
over O
time O
related O
to O
initial O
CTG O
repeat O
size O
and O
the O
time O
interval O
and O
always O
biased O
towards O
further O
expansion O
. O

Attempts O
to O
mathematically O
model O
the O
dynamics O
have O
proved O
only O
partially O
successful O
suggesting O
that O
individual O
specific O
genetic O
and O
/ O
or O
environmental O
factors O
also O
play O
a O
role O
in O
somatic O
mosaicism O
. O
. O

Aspartylglucosaminuria B
among O
Palestinian O
Arabs O
. O

Aspartylglucosaminuria B
( O
AGU B
) O
is O
a O
rare O
disorder O
of I
glycoprotein I
metabolism O
caused O
by O
the O
deficiency B
of I
the I
lysosomal I
enzyme I
aspartylglucosaminidase I
( O
AGA O
) O
. O

AGU B
is O
inherited O
as O
an O
autosomal O
recessive O
trait O
and O
occurs O
with O
a O
high O
frequency O
in O
Finland O
because O
of O
a O
founder O
effect O
. O

While O
very O
few O
patients O
with O
AGU B
have O
been O
reported O
from O
non O
- O
Finnish O
origin O
, O
we O
diagnosed O
the O
disorder O
in O
8 O
patients O
originating O
from O
3 O
unrelated O
families O
, O
all O
Palestinian O
Arabs O
from O
the O
region O
of O
Jerusalem O
. O

The O
clinical O
diagnosis O
of O
AGU B
is O
often O
difficult O
, O
in O
particular O
early O
in O
the O
course O
of O
the O
disease O
, O
and O
most O
of O
the O
patients O
are O
diagnosed O
after O
the O
age O
of O
5 O
years O
. O

However O
, O
since O
these O
patients O
excrete O
early O
large O
amounts O
of O
aspartylglucosamine O
in O
urine O
, O
biochemical O
screening O
is O
easy O
by O
urine O
chromatography O
. O
. O

Detection O
of O
heterozygous O
carriers O
of O
the O
ataxia B
- I
telangiectasia I
( O
ATM O
) O
gene O
by O
G2 O
phase O
chromosomal O
radiosensitivity O
of O
peripheral O
blood O
lymphocytes O
. O

In O
ataxia B
- I
telangiectasia I
( O
A B
- I
T I
) O
patients O
, O
mutations O
in O
a O
single O
gene O
, O
ATM O
, O
result O
in O
an O
autosomal B
recessive I
syndrome I
that O
embraces O
a O
variety O
of O
clinical O
features O
and O
manifests O
extreme O
radiosensitivity O
and O
a O
strong O
pre O
- O
disposition O
to O
malignancy B
. O

Heterozygotes O
for O
the O
ATM O
gene O
have O
no O
clinical O
expression O
of O
A B
- I
T I
but O
may O
be O
cancer B
prone I
with O
a O
moderate O
increase O
in O
in O
vitro O
radiosensitivity O
. O

We O
performed O
a O
blind O
chromosomal O
analysis O
on O
G2 O
- O
phase O
lymphocytes O
from O
7 O
unrelated O
A B
- I
T I
patients O
, O
13 O
obligate O
A B
- I
T I
heterozygotes O
( O
parents O
of O
the O
patients O
) O
, O
and O
14 O
normal O
controls O
following O
X O
- O
irradiation O
with O
1 O
Gy O
in O
order O
to O
evaluate O
this O
cytogenetic O
method O
as O
a O
tool O
for O
detection O
of O
ATM O
carriers O
. O

Both O
A B
- I
T I
homozygotes O
and O
heterozygotes O
showed O
significantly O
increased O
levels O
of O
radiation O
- O
induced O
chromatid O
damage O
relative O
to O
that O
of O
normal O
controls O
. O

These O
results O
show O
that O
the O
G2 O
- O
phase O
chromosomal O
radiosensitivity O
assay O
can O
be O
used O
for O
the O
detection O
of O
A B
- I
T I
heterozygotes O
. O

In O
combination O
with O
molecular O
genetic O
analyses O
, O
this O
test O
may O
be O
of O
value O
in O
studies O
of O
familial B
and I
sporadic I
cancers I
aimed O
at O
determination O
of O
the O
potential O
involvement O
of O
ATM O
mutations O
in O
tumor B
risk O
or O
development O
. O
. O

Ataxia B
- I
telangiectasia I
: O
identification O
and O
detection O
of O
founder O
- O
effect O
mutations O
in O
the O
ATM O
gene O
in O
ethnic O
populations O
. O

To O
facilitate O
the O
evaluation O
of O
ATM O
heterozygotes O
for O
susceptibility O
to O
other O
diseases O
, O
such O
as O
breast B
cancer I
, O
we O
have O
attempted O
to O
define O
the O
most O
common O
mutations O
and O
their O
frequencies O
in O
ataxia B
- I
telangiectasia I
( O
A B
- I
T I
) O
homozygotes O
from O
10 O
ethnic O
populations O
. O

Both O
genomic O
mutations O
and O
their O
effects O
on O
cDNA O
were O
characterized O
. O

Protein O
- O
truncation O
testing O
of O
the O
entire O
ATM O
cDNA O
detected O
92 O
( O
66 O
% O
) O
truncating O
mutations O
in O
140 O
mutant O
alleles O
screened O
. O

The O
haplotyping O
of O
patients O
with O
identical O
mutations O
indicates O
that O
almost O
all O
of O
these O
represent O
common O
ancestry O
and O
that O
very O
few O
spontaneously O
recurring O
ATM O
mutations O
exist O
. O

Assays O
requiring O
minimal O
amounts O
of O
genomic O
DNA O
were O
designed O
to O
allow O
rapid O
screening O
for O
common O
ethnic O
mutations O
. O

These O
rapid O
assays O
detected O
mutations O
in O
76 O
% O
of O
Costa O
Rican O
patients O
( O
3 O
) O
, O
50 O
% O
of O
Norwegian O
patients O
( O
1 O
) O
, O
25 O
% O
of O
Polish O
patients O
( O
4 O
) O
, O
and O
14 O
% O
of O
Italian O
patients O
( O
1 O
) O
, O
as O
well O
as O
in O
patients O
of O
Amish O
/ O
Mennonite O
and O
Irish O
English O
backgrounds O
. O

Additional O
mutations O
were O
observed O
in O
Japanese O
, O
Utah O
Mormon O
, O
and O
African O
American O
patients O
. O

These O
assays O
should O
facilitate O
screening O
for O
A B
- I
T I
heterozygotes O
in O
the O
populations O
studied O
. O
. O

The O
von B
Hippel I
- I
Lindau I
tumor I
suppressor O
gene O
is O
required O
for O
cell O
cycle O
exit O
upon O
serum O
withdrawal O
. O

The O
inactivation O
of O
the O
von B
Hippel I
- I
Lindau I
( I
VHL I
) I
tumor I
suppressor O
gene O
predisposes O
affected O
individuals O
to O
the O
human O
VHL B
cancer I
syndrome I
and O
is O
associated O
with O
sporadic B
renal I
cell I
carcinomas I
( O
RCC B
) O
and O
brain B
hemangioblastomas I
. O

VHL O
- O
negative O
786 O
- O
0 O
RCC B
cells O
are O
tumorigenic O
in O
nude O
mice O
which O
is O
suppressed O
by O
the O
reintroduction O
of O
VHL O
. O

Remarkably O
, O
this O
occurs O
without O
affecting O
the O
growth O
rate O
and O
cell O
cycle O
profile O
of O
these O
cells O
in O
culture O
. O

The O
786 O
- O
0 O
cell O
line O
, O
like O
many O
cancer B
cells O
, O
fails O
to O
exit O
the O
cell O
cycle O
upon O
serum O
withdrawal O
. O

Here O
, O
it O
is O
shown O
that O
reintroduction O
of O
the O
wild O
- O
type O
VHL B
gene O
restores O
the O
ability O
of O
VHL O
- O
negative O
RCC B
cancer I
cells O
to O
exit O
the O
cell O
cycle O
and O
enter O
G0 O
/ O
quiescence O
in O
low O
serum O
. O

Both O
VHL O
- O
positive O
and O
VHL O
- O
negative O
RCC B
cells O
exit O
the O
cell O
cycle O
by O
contact O
inhibition O
. O

The O
cyclin O
- O
dependent O
kinase O
inhibitor O
, O
p27 O
, O
accumulates O
upon O
serum O
withdrawal O
, O
only O
in O
the O
presence O
of O
VHL B
, O
as O
a O
result O
of O
the O
stabilization O
of O
the O
protein O
. O

We O
propose O
that O
the O
loss O
of O
wild O
- O
type O
VHL B
gene O
results O
in O
a O
specific O
cellular O
defect O
in O
serum O
- O
dependent O
growth O
control O
, O
which O
may O
initiate O
tumor B
formation O
. O

This O
is O
corrected O
by O
the O
reintroduction O
of O
wild O
- O
type O
VHL B
, O
implicating O
VHL B
as O
the O
first O
tumor B
suppressor O
involved O
in O
the O
regulation O
of O
cell O
cycle O
exit O
, O
which O
is O
consistent O
with O
its O
gatekeeper O
function O
in O
the O
kidney O
. O
. O

Piebaldism B
with O
deafness B
: O
molecular O
evidence O
for O
an O
expanded O
syndrome O
. O

In O
a O
South O
African O
girl O
of O
Xhosa O
stock O
with O
severe O
piebaldism B
and O
profound O
congenital B
sensorineural I
deafness I
we O
identified O
a O
novel O
missense O
substitution O
at O
a O
highly O
conserved O
residue O
in O
the O
intracellular O
kinase O
domain O
of O
the O
KIT O
proto O
- O
oncogene O
, O
R796G O
. O

Though O
auditory B
anomalies I
have O
been O
observed O
in O
mice O
with O
dominant O
white O
spotting O
( O
W O
) O
due O
to O
KIT O
mutations O
, O
deafness B
is O
not O
typical O
in O
human O
piebaldism B
. O

Thus O
, O
the O
occurrence O
of O
sensorineural B
deafness I
in O
this O
patient O
extends O
considerably O
the O
phenotypic O
range O
of O
piebaldism B
due O
to O
KIT O
gene O
mutation O
in O
humans O
and O
tightens O
the O
clinical O
similarity O
between O
piebaldism B
and O
the O
various O
forms O
of O
Waardenburg B
syndrome I
. O
. O

Cycloheximide O
facilitates O
the O
identification O
of O
aberrant O
transcripts O
resulting O
from O
a O
novel O
splice O
- O
site O
mutation O
in O
COL17A1 O
in O
a O
patient O
with O
generalized O
atrophic I
benign I
epidermolysis I
bullosa I
. O

Patients O
with O
generalized O
atrophic B
benign I
epidermolysis I
bullosa I
often O
show O
decreased O
expression O
of O
type O
XVII O
collagen O
, O
a O
transmembrane O
hemidesmosomal O
protein O
encoded O
by O
COL17A1 O
. O

This O
report O
documents O
a O
novel O
splice O
- O
site O
mutation O
in O
COL17A1 O
in O
a O
patient O
with O
generalized O
atrophic B
benign I
epidermolysis I
bullosa I
, O
and O
applies O
a O
new O
methodology O
to O
define O
and O
characterize O
the O
resulting O
mRNA O
splice O
variants O
. O

Mutational O
analysis O
of O
COL17A1 O
identified O
a O
maternally O
inherited O
G O
- O
to O
- O
T O
transversion O
at O
the O
- O
1 O
position O
of O
exon O
32 O
. O

This O
acceptor O
splice O
- O
site O
mutation O
led O
to O
the O
formation O
of O
aberrant O
transcripts O
present O
at O
extremely O
low O
levels O
. O

Based O
on O
our O
recent O
finding O
that O
cycloheximide O
stabilized O
mutant O
COL17A1 O
transcripts O
in O
keratinocytes O
homozygous O
for O
a O
frameshift O
mutation O
, O
the O
effects O
of O
the O
splice O
- O
site O
mutation O
on O
splicing O
of O
COL17A1 O
transcripts O
were O
determined O
using O
reverse O
transcriptase O
polymerase O
chain O
reaction O
of O
total O
RNA O
from O
keratinocytes O
incubated O
for O
2 O
. O

5 O
h O
in O
the O
presence O
or O
absence O
of O
10 O
microg O
cycloheximide O
per O
ml O
. O

Using O
this O
approach O
, O
an O
abnormally O
spliced O
transcript O
was O
identified O
that O
contains O
an O
extra O
264 O
bases O
upstream O
from O
exon O
32 O
, O
resulting O
in O
a O
premature O
termination O
codon O
27 O
bp O
downstream O
from O
the O
cryptic O
splice O
site O
. O

Three O
other O
splice O
variants O
, O
including O
one O
derived O
from O
the O
skipping O
of O
exon O
32 O
, O
were O
also O
identified O
. O

These O
results O
indicate O
the O
usefulness O
of O
cycloheximide O
treatment O
in O
evaluating O
the O
abnormal O
processing O
of O
mRNA O
due O
to O
splice O
- O
site O
mutations O
, O
because O
( O
i O
) O
aberrant O
splicing O
often O
generates O
a O
premature O
termination O
codon O
, O
( O
ii O
) O
transcripts O
with O
premature O
termination O
codons O
can O
occur O
at O
low O
or O
undetectable O
levels O
due O
to O
nonsense O
- O
mediated O
mRNA O
decay O
, O
and O
( O
iii O
) O
the O
levels O
of O
these O
transcripts O
can O
be O
increased O
by O
cycloheximide O
. O

A O
deletion O
mutation O
in O
COL17A1 O
in O
five O
Austrian O
families O
with O
generalized O
atrophic B
benign I
epidermolysis I
bullosa I
represents O
propagation O
of O
an O
ancestral O
allele O
. O

Patients O
with O
generalized O
atrophic B
benign I
epidermolysis I
bullosa I
, O
a O
usually O
nonlethal O
form O
of O
junctional B
epidermolysis I
bullosa I
, O
have O
generalized O
blistering B
, O
nail I
dystrophy I
, O
patchy B
alopecia I
, O
and O
dental B
abnormalities I
. O

Skin B
fragility I
in O
most O
cases O
is O
due O
to O
mutations O
in O
the O
gene O
encoding O
type O
XVII O
collagen O
( O
COL17A1 O
) O
. O

Recently O
, O
we O
reported O
five O
Austrian O
families O
with O
generalized O
atrophic B
benign I
epidermolysis I
bullosa I
who O
share O
the O
same O
COL17A1 O
mutation O
. O

Affected O
individuals O
in O
three O
families O
are O
homozygous O
for O
4003delTC O
, O
whereas O
those O
in O
two O
others O
are O
compound O
heterozygotes O
. O

To O
determine O
if O
the O
occurrence O
of O
4003delTC O
in O
these O
unrelated O
families O
signifies O
propagation O
of O
an O
ancestral O
allele O
or O
a O
mutational O
hot O
spot O
, O
haplotypes O
were O
determined O
for O
polymorphisms O
both O
within O
and O
flanking O
COL17A1 O
. O

Five O
intragenic O
polymorphisms O
were O
chosen O
based O
on O
their O
informativeness O
. O

One O
of O
these O
, O
not O
previously O
reported O
, O
was O
2988 O
A O
or O
C O
that O
introduces O
a O
new O
restriction O
site O
for O
Eco0109 O
I O
. O

All O
the O
4003delTC O
alleles O
showed O
the O
same O
haplotype O
for O
these O
five O
polymorphic O
markers O
. O

Fourteen O
microsatellite O
polymorphisms O
were O
selected O
based O
on O
their O
high O
heterozygosity O
and O
their O
location O
within O
10q23 O
- O
q25 O
near O
COL17A1 O
. O

Three O
families O
shared O
microsatellite O
polymorphisms O
covering O
at O
most O
19 O
cM O
, O
whereas O
the O
others O
shared O
smaller O
regions O
consistent O
with O
cross O
- O
over O
events O
during O
passage O
of O
this O
mutation O
through O
several O
generations O
. O

These O
results O
indicate O
that O
4003delTC O
occurs O
on O
a O
single O
ancestral O
allele O
. O
. O

The O
haptoglobin O
- O
gene O
deletion O
responsible O
for O
anhaptoglobinemia B
. O

We O
have O
found O
an O
allelic O
deletion O
of O
the O
haptoglobin O
( O
Hp O
) O
gene O
from O
an O
individual O
with O
anhaptoglobinemia B
. O

The O
Hp B
gene O
cluster O
consists O
of O
coding O
regions O
of O
the O
alpha O
chain O
and O
beta O
chain O
of O
the O
haptoglobin O
gene O
( O
Hp O
) O
and O
of O
the O
alpha O
chain O
and O
beta O
chain O
of O
the O
haptoglobin O
- O
related O
gene O
( O
Hpr O
) O
, O
in O
tandem O
from O
the O
5 O
side O
. O

Southern O
blot O
and O
PCR O
analyses O
have O
indicated O
that O
the O
individual O
with O
anhaptoglobinemia B
was O
homozygous O
for O
the O
gene O
deletion O
and O
that O
the O
gene O
deletion O
was O
included O
at O
least O
from O
the O
promoter O
region O
of O
Hp O
to O
Hpr O
alpha O
but O
not O
to O
Hpr O
beta O
( O
Hpdel O
) O
. O

In O
addition O
, O
we O
found O
seven O
individuals O
with O
hypohaptoglobinemia B
in O
three O
families O
, O
and O
the O
genotypes O
of O
six O
of O
the O
seven O
individuals O
were O
found O
to O
be O
Hp2 O
/ O
Hpdel O
. O

The O
phenotypes O
and O
genotypes O
in O
one O
of O
these O
three O
families O
showed O
the O
father O
to O
be O
hypohaptoglobinemic B
( O
Hp2 O
) O
and O
Hp2 O
/ O
Hpdel O
, O
the O
mother O
to O
be O
Hp2 O
- O
1 O
and O
Hp1 O
/ O
Hp2 O
, O
one O
of O
the O
two O
children O
to O
be O
hypohaptoglobinemic B
( O
Hp2 O
) O
and O
Hp2 O
/ O
Hpdel O
, O
and O
the O
other O
child O
to O
be O
Hp1 O
and O
Hp1 O
/ O
Hpdel O
, O
showing O
an O
anomalous O
inheritance O
of O
Hp B
phenotypes O
in O
the O
child O

with O
Hp1 O
. O

The O
Hp2 O
/ O
Hpdel O
individuals O
had O
an O
extremely O
low O
level O
of O
Hp O
( O
mean O
+ O
/ O
- O
SD O
= O
0 O
. O
049 O
+ O
/ O
- O
0 O
. O
043 O
mg O
/ O
ml O
; O
n O
= O
6 O
) O
, O
compared O
with O
the O
level O
( O
1 O
. O
64 O
+ O
/ O
- O
1 O
. O
07 O
mg O
/ O
ml O
) O
obtained O
from O
52 O
healthy O
volunteers O
having O
phenotype O
Hp2 O
, O
whereas O
the O
serum O
Hp B
level O
of O
an O
individual O
with O
Hp1 O
/ O
Hpdel O
was O
0 O
. O

50 O
mg O
/ O
ml O
, O
which O
was O
approximately O
half O
the O
level O
of O
Hp O
in O
control O
sera O
from O
the O
Hp1 O
phenotype O
( O
1 O
. O
26 O
+ O
/ O
- O
0 O
. O
33 O
mg O
/ O
ml O
; O
n O
= O
9 O
) O
, O
showing O
a O
gene O
- O
dosage O
effect O
. O

The O
other O
allele O
( O
Hp2 O
) O
of O
individuals O
with O
Hp2 O
/ O
Hpdel O
was O
found O
to O
have O
, O
in O
all O
exons O
, O
no O
mutation O
, O
by O
DNA O
sequencing O
. O

On O
the O
basis O
of O
the O
present O
study O
, O
the O
mechanism O
of O
anhaptoglobinemia B
and O
the O
mechanism O
of O
anomalous O
inheritance O
of O
Hp B
phenotypes O
were O
well O
explained O
. O

However O
, O
the O
mechanism O
of O
hypohaptoglobinemia B
remains O
unknown O

ATM O
mutations O
and O
phenotypes O
in O
ataxia B
- I
telangiectasia I
families O
in O
the O
British O
Isles O
: O
expression O
of O
mutant O
ATM O
and O
the O
risk O
of O
leukemia B
, O
lymphoma B
, O
and O
breast B
cancer I
. O

We O
report O
the O
spectrum O
of O
59 O
ATM O
mutations O
observed O
in O
ataxia B
- I
telangiectasia I
( O
A B
- I
T I
) O
patients O
in O
the O
British O
Isles O
. O

Of O
51 O
ATM O
mutations O
identified O
in O
families O
native O
to O
the O
British O
Isles O
, O
11 O
were O
founder O
mutations O
, O
and O
2 O
of O
these O
11 O
conferred O
a O
milder O
clinical O
phenotype O
with O
respect O
to O
both O
cerebellar B
degeneration I
and O
cellular O
features O
. O

We O
report O
, O
in O
two O
A B
- I
T I
families O
, O
an O
ATM O
mutation O
( O
7271T O
- O
- O
> O
G O
) O
that O
may O
be O
associated O
with O
an O
increased O
risk O
of O
breast B
cancer I
in O
both O
homozygotes O
and O
heterozygotes O
( O
relative O
risk O
12 O
. O
7 O
; O
P O
= O
. O
0025 O
) O
, O
although O
there O
is O
a O
less O
severe O
A B
- I
T I
phenotype O
in O
terms O
of O
the O
degree O
of O
cerebellar B
degeneration I
. O

This O
mutation O
( O
7271T O
- O
- O
> O
G O
) O
also O
allows O
expression O
of O
full O
- O
length O
ATM O
protein O
at O
a O
level O
comparable O
with O
that O
in O
unaffected O
individuals O
. O

In O
addition O
, O
we O
have O
studied O
18 O
A B
- I
T I
patients O
, O
in O
15 O
families O
, O
who O
developed O
leukemia B
, O
lymphoma B
, O
preleukemic B
T I
- I
cell I
proliferation I
, O
or O
Hodgkin B
lymphoma I
, O
mostly O
in O
childhood O
. O

A O
wide O
variety O
of O
ATM O
mutation O
types O
, O
including O
missense O
mutations O
and O
in O
- O
frame O
deletions O
, O
were O
seen O
in O
these O
patients O
. O

We O
also O
show O
that O
25 O
% O
of O
all O
A B
- I
T I
patients O
carried O
in O
- O
frame O
deletions O
or O
missense O
mutations O
, O
many O
of O
which O
were O
also O
associated O
with O
expression O
of O
mutant O
ATM O
protein O
. O

The O
DMPK O
gene O
of O
severely O
affected O
myotonic B
dystrophy I
patients O
is O
hypermethylated O
proximal O
to O
the O
largely O
expanded O
CTG O
repeat O
. O

Using O
methylation O
- O
sensitive O
restriction O
enzymes O
, O
we O
characterized O
the O
methylation O
pattern O
on O
the O
5 O
side O
of O
the O
CTG O
repeat O
in O
the O
DMPK O
gene O
of O
normal O
individuals O
and O
of O
patients O
affected O
with O
myotonic B
dystrophy I
, O
showing O
expansions O
of O
the O
repetitive O
sequence O
. O

The O
gene O
segment O
analyzed O
corresponds O
to O
the O
genomic O
SacI O
- O
HindIII O
fragment O
carrying O
exons O
11 O
- O
15 O
. O

There O
is O
constitutive O
methylation O
in O
intron O
12 O
at O
restriction O
sites O
of O
SacII O
and O
HhaI O
, O
localized O
1 O
, O
159 O
- O
1 O
, O
232 O
bp O
upstream O
of O
the O
CTG O
repeat O
, O
whereas O
most O
, O
if O
not O
all O
, O
of O
the O
other O
sites O
of O
SacII O
, O
HhaI O
, O
and O
HpaII O
in O
this O
region O
are O
unmethylated O
, O
in O
normal O
individuals O
and O
most O
of O
the O
patients O
. O

In O
a O
number O
of O
young O
and O
severely O
affected O
patients O
, O
however O
, O
complete O
methylation O
of O
these O
restriction O
sites O
was O
found O
in O
the O
mutated O
allele O
. O

In O
most O
of O
these O
patients O
, O
the O
onset O
of O
the O
disease O
was O
congenital O
. O

Preliminary O
in O
vivo O
footprinting O
data O
gave O
evidence O
for O
protein O
- O
DNA O
contact O
in O
normal O
genes O
at O
an O
Sp1 O
consensus O
binding O
site O
upstream O
of O
the O
CTG O
repeat O
and O
for O
a O
significant O
reduction O
of O
this O
interaction O
in O
cells O
with O
a O
hypermethylated O
DMPK O
gene O
. O
. O

The O
hemochromatosis B
gene O
product O
complexes O
with O
the O
transferrin O
receptor O
and O
lowers O
its O
affinity O
for O
ligand O
binding O
. O

We O
recently O
reported O
the O
positional O
cloning O
of O
a O
candidate O
gene O
for O
hereditary B
hemochromatosis I
called O
HFE O
. O

The O
gene O
product O
, O
a O
member O
of O
the O
major O
histocompatibility O
complex O
class O
I O
- O
like O
family O
, O
was O
found O
to O
have O
a O
mutation O
, O
Cys O
- O
282 O
- O
- O
> O
Tyr O
( O
C282Y O
) O
, O
in O
85 O
% O
of O
patient O
chromosomes O
. O

This O
mutation O
eliminates O
the O
ability O
of O
HFE O
to O
associate O
with O
beta2 O
- O
microglobulin O
( O
beta2m O
) O
and O
prevents O
cell O
- O
surface O
expression O
. O

A O
second O
mutation O
that O
has O
no O
effect O
on O
beta2m O
association O
, O
H63D O
, O
was O
found O
in O
eight O
out O
of O
nine O
patients O
heterozygous O
for O
the O
C282Y O
mutant O
. O

In O
this O
report O
, O
we O
demonstrate O
in O
cultured O
293 O
cells O
overexpressing O
wild O
- O
type O
or O
mutant O
HFE O
proteins O
that O
both O
the O
wild O
- O
type O
and O
H63D O
HFE O
proteins O
form O
stable O
complexes O
with O
the O
transferrin O
receptor O
( O
TfR O
) O
. O

The O
C282Y O
mutation O
nearly O
completely O
prevents O
the O
association O
of O
the O
mutant O
HFE O
protein O
with O
the O
TfR O
. O

Studies O
on O
cell O
- O
associated O
transferrin O
at O
37 O
degrees O
C O
suggest O
that O
the O
overexpressed O
wild O
- O
type O
HFE O
protein O
decreases O
the O
affinity O
of O
the O
TfR O
for O
transferrin O
. O

The O
overexpressed O
H63D O
protein O
does O
not O
have O
this O
effect O
, O
providing O
the O
first O
direct O
evidence O
for O
a O
functional O
consequence O
of O
the O
H63D O
mutation O
. O

Addition O
of O
soluble O
wild O
- O
type O
HFE O
/ O
beta2m O
heterodimers O
to O
cultured O
cells O
also O
decreased O
the O
apparent O
affinity O
of O
the O
TfR O
for O
its O
ligand O
under O
steady O
- O
state O
conditions O
, O
both O
in O
293 O
cells O
and O
in O
HeLa O
cells O
. O

Furthermore O
, O
at O
4 O
degrees O
C O
, O
the O
added O
soluble O
complex O
of O
HFE O
/ O
beta2m O
inhibited O
binding O
of O
transferrin O
to O
HeLa O
cell O
TfR O
in O
a O
concentration O
- O
dependent O
manner O
. O

Scatchard O
plots O
of O
these O
data O
indicate O
that O
the O
added O
heterodimer O
substantially O
reduced O
the O
affinity O
of O
TfR O
for O
transferrin O
. O

These O
results O
establish O
a O
molecular O
link O
between O
HFE O
and O
a O
key O
protein O
involved O
in O
iron O
transport O
, O
the O
TfR O
, O
and O
raise O
the O
possibility O
that O
alterations O
in O
this O
regulatory O
mechanism O
may O
play O
a O
role O
in O
the O
pathogenesis O
of O
hereditary B
hemochromatosis I
. O
. O

Genomic O
organization O
of O
the O
UBE3A O
/ O
E6 O
- O
AP O
gene O
and O
related O
pseudogenes O
. O

The O
UBE3A O
gene O
encodes O
the O
E6 O
- O
AP O
ubiquitin O
- O
protein O
ligase O
and O
has O
recently O
been O
shown O
to O
be O
mutated O
in O
Angelman B
syndrome I
patients O
who O
lack O
15q11 O
- O
q13 O
deletions O
or O
chromosome O
15 O
paternal O
uniparental I
disomy I
. O

Previous O
UBE3A O
cDNA O
analysis O
has O
shown O
a O
coding O
region O
of O
approximately O
2 O
. O

6 O
kb O
and O
a O
3 O
- O
untranslated O
region O
( O
UTR O
) O
of O
< O
50 O
bp O
, O
whereas O
Northern O
analysis O
has O
indicated O
mRNA O
sizes O
of O
5 O
- O
8 O
kb O
. O

We O
have O
analyzed O
additional O
cDNA O
clones O
and O
provide O
evidence O
for O
an O
additional O
0 O
. O

5 O
kb O
of O
5 O
- O
UTR O
and O
> O
2 O
kb O
of O
3 O
- O
UTR O
. O

We O
have O
established O
the O
genomic O
organization O
of O
UBE3A O
and O
the O
sequence O
of O
intron O
- O
exon O
borders O
. O

We O
have O
also O
mapped O
two O
highly O
homologous O
processed O
pseudogenes O
, O
UBE3AP1 O
and O
UBE3AP2 O
, O
to O
chromosomes O
2 O
and O
21 O
, O
respectively O
, O
and O
determined O
their O
genomic O
organization O
. O

These O
results O
will O
form O
the O
basis O
for O
studies O
of O
mutation O
and O
imprinting O
of O
UBE3A O
. O

Mutation O
spectrum O
and O
genotype O
- O
phenotype O
analyses O
in O
Cowden B
disease I
and O
Bannayan B
- I
Zonana I
syndrome I
, O
two O
hamartoma B
syndromes I
with O
germline O
PTEN O
mutation O
. O

The O
tumour B
suppressor O
gene O
PTEN O
, O
which O
maps O
to O
10q23 O
. O

3 O
and O
encodes O
a O
403 O
amino O
acid O
dual O
specificity O
phosphatase O
( O
protein O
tyrosine O
phosphatase O
; O
PTPase O
) O
, O
was O
shown O
recently O
to O
play O
a O
broad O
role O
in O
human O
malignancy O
. O

Somatic O
PTEN O
deletions O
and O
mutations O
were O
observed O
in O
sporadic O
breast I
, I
brain I
, I
prostate I
and I
kidney I
cancer I
cell O
lines O
and O
in O
several O
primary O
tumours B
such O
as O
endometrial B
carcinomas I
, O
malignant B
melanoma I
and O
thyroid B
tumours I
. O

In O
addition O
, O
PTEN O
was O
identified O
as O
the O
susceptibility O
gene O
for O
two O
hamartoma B
syndromes I
Cowden B
disease I
( O
CD B
; O
MIM O
158350 O
) O
and O
Bannayan B
- I
Zonana I
( O
BZS B
) O
or O
Ruvalcaba B
- I
Riley I
- I
Smith I
syndrome I
( O
MIM O
153480 O
) O
. O

Constitutive O
DNA O
from O
37 O
CD B
families O
and O
seven O
BZS B
families O
was O
screened O
for O
germline O
PTEN O
mutations O
. O

PTEN O
mutations O
were O
identified O
in O
30 O
of O
37 O
( O
81 O
% O
) O
CD B
families O
, O
including O
missense O
and O
nonsense O
point O
mutations O
, O
deletions O
, O
insertions O
, O
a O
deletion O
/ O
insertion O
and O
splice O
site O
mutations O
. O

These O
mutations O
were O
scattered O
over O
the O
entire O
length O
of O
PTEN O
, O
with O
the O
exception O
of O
the O
first O
, O
fourth O
and O
last O
exons O
. O

A O
hot O
spot O
for O
PTEN O
mutation O
in O
CD O
was O
identified O
in O
exon O
5 O
that O
contains O
the O
PTPase O
core O
motif O
, O
with O
13 O
of O
30 O
( O
43 O
% O
) O
CD B
mutations O
identified O
in O
this O
exon O
. O

Seven O
of O
30 O
( O
23 O
% O
) O
were O
within O
the O
core O
motif O
, O
the O
majority O
( O
five O
of O
seven O
) O
of O
which O
were O
missense O
mutations O
, O
possibly O
pointing O
to O
the O
functional O
significance O
of O
this O
region O
. O

Germline O
PTEN O
mutations O
were O
identified O
in O
four O
of O
seven O
( O
57 O
% O
) O
BZS B
families O
studied O
. O

Interestingly O
, O
none O
of O
these O
mutations O
was O
observed O
in O
the O
PTPase O
core O
motif O
. O

It O
is O
also O
worthy O
of O
note O
that O
a O
single O
nonsense O
point O
mutation O
, O
R233X O
, O
was O
observed O
in O
the O
germline O
DNA O
from O
two O
unrelated O
CD B
families O
and O
one O
BZS B
family O
. O

Genotype O
- O
phenotype O
studies O
were O
not O
performed O
on O
this O
small O
group O
of O
BZS B
families O
. O

However O
, O
genotype O
- O
phenotype O
analysis O
inthe O
group O
of O
CD B
families O
revealed O
two O
possible O
associations O
worthy O
of O
follow O
- O
up O
in O
independent O
analyses O
. O

The O
first O
was O
an O
association O
noted O
in O
the O
group O
of O
CD B
families O
with O
breast B
disease I
. O

A O
correlation O
was O
observed O
between O
the O
presence O
/ O
absence O
of O
a O
PTEN O
mutation O
and O
the O
type O
of O
breast O
involvement O
( O
unaffected O
versus O
benign O
versus O
malignant O
) O
. O

Specifically O
and O
more O
directly O
, O
an O
association O
was O
also O
observed O
between O
the O
presence O
of O
a O
PTEN O
mutation O
and O
malignant B
breast I
disease I
. O

Secondly O
, O
there O
appeared O
to O
be O
an O
interdependent O
association O
between O
mutations O
upstream O
and O
within O
the O
PTPase O
core O
motif O
, O
the O
core O
motif O
containing O
the O
majority O
of O
missense O
mutations O
, O
and O
the O
involvement O
of O
all O
major O
organ O
systems O
( O
central O
nervous O
system O
, O
thyroid O
, O
breast O
, O
skin O
and O
gastrointestinal O
tract O
) O
. O

However O
, O
these O
observations O
would O
need O
to O
be O
confirmed O
by O
studying O
a O
larger O
number O
of O
CD B
families O
. O

Molecular O
defects O
leading O
to O
human O
complement B
component I
C6 I
deficiency I
in O
an O
African O
- O
American O
family O
. O

Complement B
component I
C6 I
deficiency I
( O
C6D B
) O
was O
diagnosed O
in O
a O
16 O
- O
year O
- O
old O
African O
- O
American O
male O
with O
meningococcal B
meningitis I
. O

The O
patients O
father O
and O
two O
brothers O
also O
had O
C6D B
, O
but O
gave O
no O
history O
of O
meningitis B
or O
other O
neisserial B
infection I
. O

By O
using O
exon O
- O
specific O
polymerase O
chain O
reaction O
( O
PCR O
) O
/ O
single O
- O
strand O
conformation O
polymorphism O
as O
a O
screening O
step O
and O
nucleotide O
sequencing O
of O
target O
exons O
, O
we O
determined O
that O
the O
proband O
was O
a O
compound O
heterozygote O
for O
two O
C6 O
gene O
mutations O
. O

The O
first O
, O
1195delC O
located O
in O
exon O
7 O
, O
is O
a O
novel O
mutation O
, O
while O
the O
second O
, O
1936delG O
in O
exon O
12 O
, O
has O
been O
described O
before O
to O
cause O
C6D B
in O
an O
unrelated O
African O
- O
American O
individual O
. O

Both O
mutations O
result O
in O
premature O
termination O
codons O
and O
C6 O
null O
alleles O
. O

Allele O
- O
specific O
PCR O
indicated O
that O
the O
probands O
two O
brothers O
also O
inherited O
the O
1195delC O
mutation O
from O
their O
heterozygous O
mother O
and O
the O
1936delG O
mutation O
from O
their O
homozygous O
father O
. O
. O

PAX6 O
mutations O
reviewed O
. O

Mutations O
in O
PAX6 O
are O
responsible O
for O
human O
aniridia B
and O
have O
also O
been O
found O
in O
patients O
with O
Peters B
anomaly I
, O
with O
congenital B
cataracts I
, O
with O
autosomal B
dominant I
keratitis I
, O
and O
with O
isolated O
foveal B
hypoplasia I
. O

No O
locus O
other O
than O
chromosome O
11p13 O
has O
been O
implicated O
in O
aniridia B
, O
and O
PAX6 O
is O
clearly O
the O
major O
, O
if O
not O
only O
, O
gene O
responsible O
. O

Twenty O
- O
eight O
percent O
of O
identified O
PAX6 O
mutations O
are O
C O
- O
T O
changes O
at O
CpG O
dinucleotides O
, O
20 O
% O
are O
splicing O
errors O
, O
and O
more O
than O
30 O
% O
are O
deletion O
or O
insertion O
events O
. O

There O
is O
a O
noticeably O
elevated O
level O
of O
mutation O
in O
the O
paired O
domain O
compared O
with O
the O
rest O
of O
the O
gene O
. O

Increased O
mutation O
in O
the O
homeodomain O
is O
accounted O
for O
by O
the O
hypermutable O
CpG O
dinucleotide O
in O
codon O
240 O
. O

Very O
nearly O
all O
mutations O
appear O
to O
cause O
loss O
of O
function O
of O
the O
mutant O
allele O
, O
and O
more O
than O
80 O
% O
of O
exonic O
substitutions O
result O
in O
nonsense O
codons O
. O

In O
a O
gene O
with O
such O
extraordinarily O
high O
sequence O
conservation O
throughout O
evolution O
, O
there O
are O
presumed O
undiscovered O
missense O
mutations O
, O
these O
are O
hypothesized O
to O
exist O
in O
as O
- O
yet O
unidentified O
phenotypes O
. O
. O

Genetic O
heterogeneity O
and O
penetrance O
analysis O
of O
the O
BRCA1 O
and O
BRCA2 O
genes O
in O
breast B
cancer I
families O
. O

The O
Breast B
Cancer I
Linkage O
Consortium O
. O

The O
contribution O
of O
BRCA1 O
and O
BRCA2 O
to O
inherited B
breast I
cancer I
was O
assessed O
by O
linkage O
and O
mutation O
analysis O
in O
237 O
families O
, O
each O
with O
at O
least O
four O
cases O
of O
breast B
cancer I
, O
collected O
by O
the O
Breast B
Cancer I
Linkage O
Consortium O
. O

Families O
were O
included O
without O
regard O
to O
the O
occurrence O
of O
ovarian B
or I
other I
cancers I
. O

Overall O
, O
disease O
was O
linked O
to O
BRCA1 O
in O
an O
estimated O
52 O
% O
of O
families O
, O
to O
BRCA2 O
in O
32 O
% O
of O
families O
, O
and O
to O
neither O
gene O
in O
16 O
% O
( O
95 O
% O
confidence O
interval O
[ O
CI O
] O
6 O
% O
- O
28 O
% O
) O
, O
suggesting O
other O
predisposition O
genes O
. O

The O
majority O
( O
81 O
% O
) O
of O
the O
breast B
- I
ovarian I
cancer I
families O
were O
due O
to O
BRCA1 O
, O
with O
most O
others O
( O
14 O
% O
) O
due O
to O
BRCA2 O
. O

Conversely O
, O
the O
majority O
of O
families O
with O
male B
and I
female I
breast I
cancer I
were O
due O
to O
BRCA2 O
( O
76 O
% O
) O
. O

The O
largest O
proportion O
( O
67 O
% O
) O
of O
families O
due O
to O
other O
genes O
was O
found O
in O
families O
with O
four O
or O
five O
cases O
of O
female B
breast I
cancer I
only O
. O

These O
estimates O
were O
not O
substantially O
affected O
either O
by O
changing O
the O
assumed O
penetrance O
model O
for O
BRCA1 O
or O
by O
including O
or O
excluding O
BRCA1 O
mutation O
data O
. O

Among O
those O
families O
with O
disease O
due O
to O
BRCA1 O
that O
were O
tested O
by O
one O
of O
the O
standard O
screening O
methods O
, O
mutations O
were O
detected O
in O
the O
coding O
sequence O
or O
splice O
sites O
in O
an O
estimated O
63 O
% O
( O
95 O
% O
CI O
51 O
% O
- O
77 O
% O
) O
. O

The O
estimated O
sensitivity O
was O
identical O
for O
direct O
sequencing O
and O
other O
techniques O
. O

The O
penetrance O
of O
BRCA2 O
was O
estimated O
by O
maximizing O
the O
LOD O
score O
in O
BRCA2 O
- O
mutation O
families O
, O
over O
all O
possible O
penetrance O
functions O
. O

The O
estimated O
cumulative O
risk O
of O
breast B
cancer I
reached O
28 O
% O
( O
95 O
% O
CI O
9 O
% O
- O
44 O
% O
) O
by O
age O
50 O
years O
and O
84 O
% O
( O
95 O
% O
CI O
43 O
% O
- O
95 O
% O
) O
by O
age O
70 O
years O
. O

The O
corresponding O
ovarian B
cancer I
risks O
were O
0 O
. O

4 O
% O
( O
95 O
% O
CI O
0 O
% O
- O
1 O
% O
) O
by O
age O
50 O
years O
and O
27 O
% O
( O
95 O
% O
CI O
0 O
% O
- O
47 O
% O
) O
by O
age O
70 O
years O
. O

The O
lifetime O
risk O
of O
breast B
cancer I
appears O
similar O
to O
the O
risk O
in O
BRCA1 O
carriers O
, O
but O
there O
was O
some O
suggestion O
of O
a O
lower O
risk O
in O
BRCA2 O
carriers O
< O
50 O
years O
of O
age O
. O

Eye B
movement I
abnormalities I
correlate O
with O
genotype O
in O
autosomal B
dominant I
cerebellar I
ataxia I
type I
I I
. O

We O
compared O
horizontal O
eye O
movements O
( O
visually O
guided O
saccades O
, O
antisaccades O
, O
and O
smooth O
pursuit O
) O
in O
control O
subjects O
( O
n O
= O
14 O
) O
and O
patients O
with O
three O
forms O
of O
autosomal B
dominant I
cerebellar I
ataxias I
type I
I I
spinocerebellar I
ataxias I
1 I
and I
2 I
( O
SCA1 B
, O
n O
= O
11 O
; O
SCA2 B
, O
n O
= O
10 O
) O
and O
SCA3 B
/ I
Machado I
- I
Joseph I
disease I
( O
MJD B
) O
( O
n O
= O
16 O
) O
. O

In O
SCA1 O
, O
saccade O
amplitude O
was O
significantly O
increased O
, O
resulting O
in O
hypermetria B
. O

The O
smooth O
pursuit O
gain O
was O
decreased O
. O

In O
SCA2 O
, O
saccade O
velocity O
was O
markedly O
decreased O
. O

The O
percentage O
of O
errors O
in O
antisaccades O
was O
greatly O
increased O
and O
was O
significantly O
correlated O
with O
age O
at O
disease O
onset O
. O

In O
addition O
, O
a O
correlation O
between O
smooth O
pursuit O
gain O
and O
the O
number O
of O
trinucleotide O
repeats O
was O
found O
. O

In O
SCA3 O
, O
gaze O
- O
evoked O
nystagmus B
was O
often O
present O
as O
was O
saccade B
hypometria I
and O
smooth O
pursuit O
gain O
was O
markedly O
decreased O
. O

Three O
major O
criteria O
, O
saccade O
amplitude O
, O
saccade O
velocity O
, O
and O
presence O
of O
gaze O
- O
evoked O
nystagmus B
, O
permitted O
the O
correct O
assignment O
of O
90 O
% O
of O
the O
SCA1 O
, O
90 O
% O
of O
the O
SCA2 O
, O
and O
93 O
% O
of O
the O
patients O
with O
SCA3 B
to O
their O
genetically O
confirmed O
patient O
group O
and O
, O
therefore O
, O
may O
help O
orient O
diagnoses O
of O
SCA1 O
, O
SCA2 O
, O
and O
SCA3 B
at O
early O
clinical O
stages O
of O
the O
diseases O
. O
. O

Genetic O
basis O
and O
molecular O
mechanism O
for O
idiopathic B
ventricular I
fibrillation I
. O

Ventricular B
fibrillation I
causes O
more O
than O
300 O
, O
000 O
sudden O
deaths O
each O
year O
in O
the O
USA O
alone O
. O

In O
approximately O
5 O
- O
12 O
% O
of O
these O
cases O
, O
there O
are O
no O
demonstrable O
cardiac O
or O
non O
- O
cardiac O
causes O
to O
account O
for O
the O
episode O
, O
which O
is O
therefore O
classified O
as O
idiopathic B
ventricular I
fibrillation I
( O
IVF B
) O
. O

A O
distinct O
group O
of O
IVF B
patients O
has O
been O
found O
to O
present O
with O
a O
characteristic O
electrocardiographic O
pattern O
. O

Because O
of O
the O
small O
size O
of O
most O
pedigrees O
and O
the O
high O
incidence O
of O
sudden B
death I
, O
however O
, O
molecular O
genetic O
studies O
of O
IVF B
have O
not O
yet O
been O
done O
. O

Because O
IVF B
causes O
cardiac B
rhythm I
disturbance I
, O
we O
investigated O
whether O
malfunction O
of O
ion O
channels O
could O
cause O
the O
disorder O
by O
studying O
mutations O
in O
the O
cardiac O
sodium O
channel O
gene O
SCN5A O
. O

We O
have O
now O
identified O
a O
missense O
mutation O
, O
a O
splice O
- O
donor O
mutation O
, O
and O
a O
frameshift O
mutation O
in O
the O
coding O
region O
of O
SCN5A O
in O
three O
IVF B
families O
. O

We O
show O
that O
sodium O
channels O
with O
the O
missense O
mutation O
recover O
from O
inactivation O
more O
rapidly O
than O
normal O
and O
that O
the O
frameshift O
mutation O
causes O
the O
sodium O
channel O
to O
be O
non O
- O
functional O
. O

Our O
results O
indicate O
that O
mutations O
in O
cardiac O
ion O
- O
channel O
genes O
contribute O
to O
the O
risk O
of O
developing O
IVF B
. O
. O

Molecular O
heterogeneity O
in O
mucopolysaccharidosis B
IVA I
in O
Australia O
and O
Northern O
Ireland O
: O
nine O
novel O
mutations O
including O
T312S O
, O
a O
common O
allele O
that O
confers O
a O
mild O
phenotype O
. O

Mucopolysaccharidosis B
IVA I
( O
MPS B
IVA I
) O
is O
an O
autosomal B
recessive I
lysosomal I
storage I
disorder I
caused O
by O
a O
genetic B
defect I
in I
N I
- I
acetylgalactosamine I
- I
6 I
- I
sulfate I
sulfatase I
( O
GALNS O
) O
. O

Previous O
studies O
of O
patients O
from O
a O
British O
- O
Irish O
population O
showed O
that O
the O
I113F O
mutation O
is O
the O
most O
common O
single O
mutation O
among O
MPS B
IVA I
patients O
and O
produces O
a O
severe O
clinical O
phenotype O
. O

We O
studied O
mutations O
in O
the O
GALNS O
gene O
from O
23 O
additional O
MPS B
IVA I
patients O
( O
15 O
from O
Australia O
, O
8 O
from O
Northern O
Ireland O
) O
, O
with O
various O
clinical O
phenotypes O
( O
severe O
, O
16 O
cases O
; O
intermediate O
, O
4 O
cases O
; O
mild O
, O
3 O
cases O
) O
. O

We O
found O
two O
common O
mutations O
that O
together O
accounted O
for O
32 O
% O
of O
the O
44 O
unrelated O
alleles O
in O
these O
patients O
. O

One O
is O
the O
T312S O
mutation O
, O
a O
novel O
mutation O
found O
exclusively O
in O
milder O
patients O
. O

The O
other O
is O
the O
previously O
described O
I113F O
that O
produces O
a O
severe O
phenotype O
. O

The O
I113F O
and O
T312S O
mutations O
accounted O
for O
8 O
( O
18 O
% O
) O
and O
6 O
( O
14 O
% O
) O
of O
44 O
unrelated O
alleles O
, O
respectively O
. O

The O
relatively O
high O
residual O
GALNS O
activity O
seen O
when O
the O
T312S O
mutant O
cDNA O
is O
overexpressed O
in O
mutant O
cells O
provides O
an O
explanation O
for O
the O
mild O
phenotype O
in O
patients O
with O
this O
mutation O
. O

The O
distribution O
and O
relative O
frequencies O
of O
the O
I113F O
and O
T312S O
mutations O
in O
Australia O
corresponded O
to O
those O
observed O
in O
Northern O
Ireland O
and O
are O
unique O
to O
these O
two O
populations O
, O
suggesting O
that O
both O
mutations O
were O
probably O
introduced O
to O
Australia O
by O
Irish O
migrants O
during O
the O
19th O
century O
. O

Haplotype O
analysis O
using O
6 O
RFLPs O
provides O
additional O
data O
that O
the O
I113F O
mutation O
originated O
from O
a O
common O
ancestor O
. O

The O
other O
9 O
novel O
mutations O
identified O
in O
these O
23 O
patients O
were O
each O
limited O
to O
a O
single O
family O
. O

These O
data O
provide O
further O
evidence O
for O
extensive O
allelic O
heterogeneity O
in O
MPS B
IVA I
in O
British O
- O
Irish O
patients O
and O
provide O
evidence O
for O
their O
transmission O
to O
Australia O
by O
British O
- O
Irish O
migrants O
. O
. O

Identification O
of O
constitutional O
WT1 O
mutations O
, O
in O
patients O
with O
isolated O
diffuse I
mesangial I
sclerosis I
, O
and O
analysis O
of O
genotype O
/ O
phenotype O
correlations O
by O
use O
of O
a O
computerized O
mutation O
database O
. O

Constitutional O
mutations O
of O
the O
WT1 O
gene O
, O
encoding O
a O
zinc O
- O
finger O
transcription O
factor O
involved O
in O
renal O
and O
gonadal O
development O
, O
are O
found O
in O
most O
patients O
with O
Denys B
- I
Drash I
syndrome I
( O
DDS B
) O
, O
or O
diffuse B
mesangial I
sclerosis I
( O
DMS B
) O
associated O
with O
pseudohermaphroditism B
and O
/ O
or O
Wilms B
tumor I
( O
WT B
) O
. O

Most O
mutations O
in O
DDS B
patients O
lie O
in O
exon O
8 O
or O
exon O
9 O
, O
encoding O
zinc O
finger O
2 O
or O
zinc O
finger O
3 O
, O
respectively O
, O
with O
a O
hot O
spot O
( O
R394W O
) O
in O
exon O
9 O
. O

We O
analyzed O
a O
series O
of O
24 O
patients O
, O
10 O
with O
isolated O
DMS B
( O
IDMS B
) O
, O
10 O
with O
DDS B
, O
and O
4 O
with O
urogenital B
abnormalities I
and O
/ O
or O
WT B
. O

We O
report O
WT1 O
heterozygous O
mutations O
in O
16 O
patients O
, O
4 O
of O
whom O
presented O
with O
IDMS B
. O

One O
male O
and O
two O
female O
IDMS B
patients O
with O
WT1 O
mutations O
underwent O
normal O
puberty O
. O

Two O
mutations O
associated O
with O
IDMS B
are O
different O
from O
those O
described O
in O
DDS B
patients O
. O

No O
WT1 O
mutations O
were O
detected O
in O
the O
six O
other O
IDMS B
patients O
, O
suggesting O
genetic O
heterogeneity O
of O
this O
disease O
. O

We O
analyzed O
genotype O
/ O
phenotype O
correlations O
, O
on O
the O
basis O
of O
the O
constitution O
of O
a O
WT1 O
mutation O
database O
of O
84 O
germ O
- O
line O
mutations O
, O
to O
compare O
the O
distribution O
and O
type O
of O
mutations O
, O
according O
to O
the O
different O
symptoms O
. O

This O
demonstrated O
( O
1 O
) O
the O
association O
between O
mutations O
in O
exons O
8 O
and O
9 O
and O
DMS B
; O
( O
2 O
) O
among O
patients O
with O
DMS B
, O
a O
higher O
frequency O
of O
exon O
8 O
mutations O
among O
46 O
, O
XY O
patients O
with O
female O
phenotype O
than O
among O
46 O
, O
XY O
patients O
with O
sexual B
ambiguity I
or O
male O
phenotype O
; O
and O
( O
3 O
) O
statistically O
significant O
evidence O
that O
mutations O
in O
exons O
8 O
and O
9 O
preferentially O
affect O
amino O
acids O
with O
different O
functions O
. O
. O

The O
185delAG O
BRCA1 O
mutation O
originated O
before O
the O
dispersion O
of O
Jews O
in O
the O
diaspora O
and O
is O
not O
limited O
to O
Ashkenazim O
. O

The O
185delAG O
mutation O
in O
BRCA1 O
is O
detected O
in O
Ashkenazi O
Jews O
both O
in O
familial B
breast I
and I
ovarian I
cancer I
and O
in O
the O
general O
population O
. O

All O
tested O
Ashkenazi O
mutation O
carriers O
share O
the O
same O
allelic O
pattern O
at O
the O
BRCA1 O
locus O
. O

Our O
previous O
study O
showed O
that O
this O
Ashkenazi O
mutation O
also O
occurs O
in O
Iraqi O
Jews O
with O
a O
similar O
allelic O
pattern O
. O

We O
extended O
our O
analysis O
to O
other O
non O
- O
Ashkenazi O
subsets O
354 O
of O
Moroccan O
origin O
, O
200 O
Yemenites O
and O
150 O
Iranian O
Jews O
. O

Heteroduplex O
analysis O
complemented O
by O
direct O
DNA O
sequencing O
of O
abnormally O
migrating O
bands O
were O
employed O
. O

Four O
of O
Moroccan O
origin O
( O
1 O
. O
1 O
% O
) O
and O
none O
of O
the O
Yemenites O
or O
Iranians O
was O
a O
carrier O
of O
the O
185delAG O
mutation O
. O

BRCA1 O
allelic O
patterns O
were O
determined O
for O
four O
of O
these O
individuals O
and O
for O
12 O
additional O
non O
- O
Ashkenazi O
185delAG O
mutation O
carriers O
who O
had O
breast B
/ I
ovarian I
cancer I
. O

Six O
non O
- O
Ashkenazi O
individuals O
shared O
the O
common O
Ashkenazi O
haplotype O
, O
four O
had O
a O
closely O
related O
pattern O
, O
and O
the O
rest O
( O
n O
= O
6 O
) O
displayed O
a O
distinct O
BRCA1 O
allelic O
pattern O
. O

We O
conclude O
that O
the O
185delAG O
BRCA1 O
mutation O
occurs O
in O
some O
non O
- O
Ashkenazi O
populations O
at O
rates O
comparable O
with O
that O
of O
Ashkenazim O
. O

The O
majority O
of O
Jewish O
185delAG O
mutation O
carriers O
have O
a O
common O
allelic O
pattern O
, O
supporting O
the O
founder O
effect O
notion O
, O
but O
dating O
the O
mutations O
origin O
to O
an O
earlier O
date O
than O
currently O
estimated O
. O

However O
, O
the O
different O
allelic O
pattern O
at O
the O
BRCA1 O
locus O
even O
in O
some O
Jewish O
mutation O
carriers O
, O
might O
suggest O
that O
the O
mutation O
arose O
independently O
. O
. O

Crystal O
structure O
of O
the O
hemochromatosis B
protein O
HFE O
and O
characterization O
of O
its O
interaction O
with O
transferrin O
receptor O
. O

HFE O
is O
an O
MHC O
- O
related O
protein O
that O
is O
mutated O
in O
the O
iron B
- I
overload I
disease I
hereditary B
hemochromatosis I
. O

HFE O
binds O
to O
transferrin O
receptor O
( O
TfR O
) O
and O
reduces O
its O
affinity O
for O
iron O
- O
loaded O
transferrin O
, O
implicating O
HFE O
in O
iron O
metabolism O
. O

The O
2 O
. O

6 O
A O
crystal O
structure O
of O
HFE O
reveals O
the O
locations O
of O
hemochromatosis B
mutations O
and O
a O
patch O
of O
histidines O
that O
could O
be O
involved O
in O
pH O
- O
dependent O
interactions O
. O

We O
also O
demonstrate O
that O
soluble O
TfR O
and O
HFE O
bind O
tightly O
at O
the O
basic O
pH O
of O
the O
cell O
surface O
, O
but O
not O
at O
the O
acidic O
pH O
of O
intracellular O
vesicles O
. O

TfR O
HFE O
stoichiometry O
( O
2 O
1 O
) O
differs O
from O
TfR O
transferrin O
stoichiometry O
( O
2 O
2 O
) O
, O
implying O
a O
different O
mode O
of O
binding O
for O
HFE O
and O
transferrin O
to O
TfR O
, O
consistent O
with O
our O
demonstration O
that O
HFE O
, O
transferrin O
, O
and O
TfR O
form O
a O
ternary O
complex O
. O

Identification O
of O
three O
novel O
mutations O
and O
a O
high O
frequency O
of O
the O
Arg778Leu O
mutation O
in O
Korean O
patients O
with O
Wilson B
disease I
. O

Four O
mutations O
- O
- O
R778L O
, O
A874V O
, O
L1083F O
, O
and O
2304delC O
- O
- O
in O
the O
copper O
- O
transporting O
enzyme O
, O
P O
- O
type O
ATPase O
( O
ATP7B O
) O
, O
were O
identified O
in O
Korean O
Patients O
with O
Wilson B
disease I
. O

Arg778Leu O
, O
the O
most O
frequently O
reported O
mutation O
of O
this O
enzyme O
, O
was O
found O
in O
six O
of O
eight O
unrelated O
patients O
studied O
, O
an O
allele O
frequency O
of O
37 O
. O

5 O
% O
, O
which O
is O
considerably O
higher O
than O
those O
in O
other O
Asian O
populations O
. O

The O
novel O
single O
nucleotide O
deletion O
, O
2304delC O
, O
was O
found O
in O
one O
patient O
. O

Since O
a O
mutation O
at O
cDNA O
nucleotide O
2302 O
( O
2302insC O
) O
had O
been O
previously O
described O
, O
this O
region O
of O
the O
ATP7B O
gene O
may O
be O
susceptible O
to O
gene O
rearrangements O
causing O
Wilson B
disease I
. O

Disruption O
of O
splicing O
regulated O
by O
a O
CUG O
- O
binding O
protein O
in O
myotonic B
dystrophy I
. O

Myotonic B
dystrophy I
( O
DM B
) O
is O
caused O
by O
a O
CTG O
expansion O
in O
the O
3 O
untranslated O
region O
of O
the O
DM B
gene O
. O

One O
model O
of O
DM B
pathogenesis O
suggests O
that O
RNAs O
from O
the O
expanded O
allele O
create O
a O
gain O
- O
of O
- O
function O
mutation O
by O
the O
inappropriate O
binding O
of O
proteins O
to O
the O
CUG O
repeats O
. O

Data O
presented O
here O
indicate O
that O
the O
conserved O
heterogeneous O
nuclear O
ribonucleoprotein O
, O
CUG O
- O
binding O
protein O
( O
CUG O
- O
BP O
) O
, O
may O
mediate O
the O
trans O
- O
dominant O
effect O
of O
the O
RNA O
. O

CUG O
- O
BP O
was O
found O
to O
bind O
to O
the O
human O
cardiac O
troponin O
T O
( O
cTNT O
) O
pre O
- O
messenger O
RNA O
and O
regulate O
its O
alternative O
splicing O
. O

Splicing O
of O
cTNT O
was O
disrupted O
in O
DM B
striated O
muscle O
and O
in O
normal O
cells O
expressing O
transcripts O
that O
contain O
CUG O
repeats O
. O

Altered O
expression O
of O
genes O
regulated O
posttranscriptionally O
by O
CUG O
- O
BP O
therefore O
may O
contribute O
to O
DM B
pathogenesis O
. O
. O

Identification O
of O
a O
novel O
nonsense O
mutation O
and O
a O
missense O
substitution O
in O
the O
vasopressin O
- O
neurophysin O
II O
gene O
in O
two O
Spanish O
kindreds O
with O
familial B
neurohypophyseal I
diabetes I
insipidus I
. O

Familial B
neurohypophyseal I
diabetes I
insipidus I
( O
FNDI B
) O
is O
an O
autosomal B
dominant I
disease I
caused O
by O
deficiency B
in I
the I
antidiuretic I
hormone I
arginine I
vasopressin I
( O
AVP O
) O
encoded O
by O
the O
AVP O
- O
neurophysin O
II O
( O
AVP O
- O
NPII O
) O
gene O
on O
chromosome O
20p13 O
. O

In O
this O
study O
, O
we O
analyzed O
two O
families O
with O
FNDI B
using O
direct O
automated O
fluorescent O
, O
solid O
phase O
, O
single O
- O
stranded O
DNA O
sequencing O
of O
PCR O
- O
amplified O
AVP O
- O
NPII O
DNA O
. O

In O
one O
of O
the O
families O
, O
affected O
individuals O
presented O
a O
novel O
nonsense O
mutation O
in O
exon O
3 O
of O
the O
gene O
, O
consisting O
in O
a O
G O
to O
T O
transition O
at O
nucleotide O
2101 O
, O
which O
produces O
a O
stop O
signal O
in O
codon O
82 O
( O
Glu O
) O
of O
NPII O
. O

The O
premature O
termination O
eliminates O
part O
of O
the O
C O
- O
terminal O
domain O
of O
NPII O
, O
including O
a O
cysteine O
residue O
in O
position O
85 O
, O
which O
could O
be O
involved O
in O
the O
correct O
folding O
of O
the O
prohormone O
. O

In O
the O
second O
family O
, O
a O
G279A O
substitution O
at O
position O
- O
1 O
of O
the O
signal O
peptide O
was O
observed O
in O
all O
affected O
individuals O
. O

This O
missense O
mutation O
, O
which O
replaces O
Ala O
with O
Thr O
, O
is O
frequent O
among O
FNDI B
patients O
and O
is O
thought O
to O
reduce O
the O
efficiency O
of O
cleavage O
by O
signal O
peptidases O
. O
. O

Genetic O
heterogeneity O
of O
Saethre B
- I
Chotzen I
syndrome I
, O
due O
to O
TWIST O
and O
FGFR O
mutations O
. O

Thirty O
- O
two O
unrelated O
patients O
with O
features O
of O
Saethre B
- I
Chotzen I
syndrome I
, O
a O
common O
autosomal B
dominant I
condition I
of O
craniosynostosis B
and O
limb B
anomalies I
, O
were O
screened O
for O
mutations O
in O
TWIST O
, O
FGFR2 O
, O
and O
FGFR3 O
. O

Nine O
novel O
and O
three O
recurrent O
TWIST O
mutations O
were O
found O
in O
12 O
families O
. O

Seven O
families O
were O
found O
to O
have O
the O
FGFR3 O
P250R O
mutation O
, O
and O
one O
individual O
was O
found O
to O
have O
an O
FGFR2 O
VV269 O
- O
270 O
deletion O
. O

To O
date O
, O
our O
detection O
rate O
for O
TWIST O
or O
FGFR O
mutations O
is O
68 O
% O
in O
our O
Saethre B
- I
Chotzen I
syndrome I
patients O
, O
including O
our O
five O
patients O
elsewhere O
reported O
with O
TWIST O
mutations O
. O

More O
than O
35 O
different O
TWIST O
mutations O
are O
now O
known O
in O
the O
literature O
. O

The O
most O
common O
phenotypic O
features O
, O
present O
in O
more O
than O
a O
third O
of O
our O
patients O
with O
TWIST O
mutations O
, O
are O
coronal B
synostosis I
, O
brachycephaly B
, O
low B
frontal I
hairline I
, O
facial B
asymmetry I
, O
ptosis B
, O
hypertelorism B
, O
broad B
great I
toes I
, O
and O
clinodactyly B
. O

Significant O
intra O
- O
and O
interfamilial O
phenotypic O
variability O
is O
present O
for O
either O
TWIST O
mutations O
or O
FGFR O
mutations O
. O

The O
overlap O
in O
clinical O
features O
and O
the O
presence O
, O
in O
the O
same O
genes O
, O
of O
mutations O
for O
more O
than O
one O
craniosynostotic B
condition I
- O
such O
as O
Saethre B
- I
Chotzen I
, O
Crouzon B
, O
and O
Pfeiffer B
syndromes I
- O
support O
the O
hypothesis O
that O
TWIST O
and O
FGFRs O
are O
components O
of O
the O
same O
molecular O
pathway O
involved O
in O
the O
modulation O
of O
craniofacial O
and O
limb O
development O
in O
humans O
. O
. O

Mutation O
analysis O
of O
UBE3A O
in O
Angelman B
syndrome I
patients O
. O

Angelman B
syndrome I
( O
AS B
) O
is O
caused O
by O
chromosome O
15q11 O
- O
q13 O
deletions O
of O
maternal O
origin O
, O
by O
paternal B
uniparental I
disomy I
( O
UPD B
) O
15 I
, O
by O
imprinting O
defects O
, O
and O
by O
mutations O
in O
the O
UBE3A O
gene O
. O

UBE3A O
encodes O
a O
ubiquitin O
- O
protein O
ligase O
and O
shows O
brain O
- O
specific O
imprinting O
. O

Here O
we O
describe O
UBE3A O
coding O
- O
region O
mutations O
detected O
by O
SSCP O
analysis O
in O
13 O
AS B
individuals O
or O
families O
. O

Two O
identical O
de O
novo O
5 O
- O
bp O
duplications O
in O
exon O
16 O
were O
found O
. O

Among O
the O
other O
11 O
unique O
mutations O
, O
8 O
were O
small O
deletions O
or O
insertions O
predicted O
to O
cause O
frameshifts O
, O
1 O
was O
a O
mutation O
to O
a O
stop O
codon O
, O
1 O
was O
a O
missense O
mutation O
, O
and O
1 O
was O
predicted O
to O
cause O
insertion O
of O
an O
isoleucine O
in O
the O
hect O
domain O
of O
the O
UBE3A O
protein O
, O
which O
functions O
in O
E2 O
binding O
and O
ubiquitin O
transfer O
. O

Eight O
of O
the O
cases O
were O
familial O
, O
and O
five O
were O
sporadic O
. O

In O
two O
familial O
cases O
and O
one O
sporadic O
case O
, O
mosaicism O
for O
UBE3A O
mutations O
was O
detected O
in O
the O
mother O
of O
three O
AS B
sons O
, O
in O
the O
maternal O
grandfather O
of O
two O
AS B
first O
cousins O
, O
and O
in O
the O
mother O
of O
an O
AS B
daughter O
. O

The O
frequencies O
with O
which O
we O
detected O
mutations O
were O
5 O
( O
14 O
% O
) O
of O
35 O
in O
sporadic O
cases O
and O
8 O
( O
80 O
% O
) O
of O
10 O
in O
familial O
cases O
. O
. O

The O
hemochromatosis B
845 O
G O
- O
- O
> O
A O
and O
187 O
C O
- O
- O
> O
G O
mutations O
: O
prevalence O
in O
non O
- O
Caucasian O
populations O
. O

Hemochromatosis B
, O
the O
inherited B
disorder I
of I
iron I
metabolism I
, O
leads O
, O
if O
untreated O
, O
to O
progressive O
iron B
overload I
and O
premature O
death I
. O

The O
hemochromatosis B
gene O
, O
HFE O
, O
recently O
has O
been O
identified O
, O
and O
characterization O
of O
this O
gene O
has O
shown O
that O
it O
contains O
two O
mutations O
that O
result O
in O
amino O
acid O
substitutions O
- O
cDNA O
nucleotides O
845 O
G O
- O
- O
> O
A O
( O
C282Y O
) O
and O
187 O
C O
- O
- O
> O
G O
( O
H63D O
) O
. O

Although O
hemochromatosis B
is O
common O
in O
Caucasians O
, O
affecting O
> O
= O
1 O
/ O
300 O
individuals O
of O
northern O
European O
origin O
, O
it O
has O
not O
been O
recognized O
in O
other O
populations O
. O

The O
present O
study O
used O
PCR O
and O
restriction O
- O
enzyme O
digestion O
to O
analyze O
the O
frequency O
of O
the O
845 O
G O
- O
- O
> O
A O
and O
187 O
C O
- O
- O
> O
G O
mutations O
in O
HLA O
- O
typed O
samples O
from O
non O
- O
Caucasian O
populations O
, O
comprising O
Australian O
Aboriginal O
, O
Chinese O
, O
and O
Pacific O
Islanders O
. O

Results O
showed O
that O
the O
845 O
G O
- O
- O
> O
A O
mutation O
was O
present O
in O
these O
populations O
( O
allele O
frequency O
0 O
. O
32 O
% O
) O
, O
and O
, O
furthermore O
, O
it O
was O
always O
seen O
in O
conjunction O
with O
HLA O
haplotypes O
common O
in O
Caucasians O
, O
suggesting O
that O
845 O
G O
- O
- O
> O
A O
may O
have O
been O
introduced O
into O
these O
populations O
by O
Caucasian O
admixture O
. O

187 O
C O
- O
- O
> O
G O
was O
present O
at O
an O
allele O
frequency O
of O
2 O
. O

68 O
% O
in O
the O
two O
populations O
analyzed O
( O
Australian O
Aboriginal O
and O
Chinese O
) O
. O

In O
the O
Australian O
Aboriginal O
samples O
, O
187 O
C O
- O
- O
> O
G O
was O
found O
to O
be O
associated O
with O
HLA O
haplotypes O
common O
in O
Caucasians O
, O
suggesting O
that O
it O
was O
introduced O
by O
recent O
admixture O
. O

In O
the O
Chinese O
samples O
analyzed O
, O
187 O
C O
- O
- O
> O
G O
was O
present O
in O
association O
with O
a O
wide O
variety O
of O
HLA O
haplotypes O
, O
showing O
this O
mutation O
to O
be O
widespread O
and O
likely O
to O
predate O
the O
more O
genetically O
restricted O
845 O
G O
- O
- O
> O
A O
mutation O
. O

Genotype O
- O
phenotype O
correlations O
in O
attenuated B
adenomatous I
polyposis I
coli I
. O

Germ O
- O
line O
mutations O
of O
the O
tumor B
suppressor O
APC O
are O
implicated O
in O
attenuated B
adenomatous I
polyposis I
coli I
( O
AAPC B
) O
, O
a O
variant O
of O
familial B
adenomatous I
polyposis I
( O
FAP B
) O
. O

AAPC B
is O
recognized O
by O
the O
occurrence O
of O
< O
100 O
colonic B
adenomas I
and O
a O
later O
onset O
of O
colorectal B
cancer I
( O
age O
> O
40 O
years O
) O
. O

The O
aim O
of O
this O
study O
was O
to O
assess O
genotype O
- O
phenotype O
correlations O
in O
AAPC B
families O
. O

By O
protein O
- O
truncation O
test O
( O
PTT O
) O
assay O
, O
the O
entire O
coding O
region O
of O
the O
APC B
gene O
was O
screened O
in O
affected O
individuals O
from O
11 O
AAPC B
kindreds O
, O
and O
their O
phenotypic O
differences O
were O
examined O
. O

Five O
novel O
germ O
- O
line O
APC B
mutations O
were O
identified O
in O
seven O
kindreds O
. O

Mutations O
were O
located O
in O
three O
different O
regions O
of O
the O
APC B
gene O
( O
1 O
) O
at O
the O
5 O
end O
spanning O
exons O
4 O
and O
5 O
, O
( O
2 O
) O
within O
exon O
9 O
, O
and O
( O
3 O
) O
at O
the O
3 O
distal O
end O
of O
the O
gene O
. O

Variability O
in O
the O
number O
of O
colorectal B
adenomas I
was O
most O
apparent O
in O
individuals O
with O
mutations O
in O
region O
1 O
, O
and O
upper B
- I
gastrointestinal I
manifestations I
were O
more O
severe O
in O
them O
. O

In O
individuals O
with O
mutations O
in O
either O
region O
2 O
or O
region O
3 O
, O
the O
average O
number O
of O
adenomas B
tended O
to O
be O
lower O
than O
those O
in O
individuals O
with O
mutations O
in O
region O
1 O
, O
although O
age O
at O
diagnosis O
was O
similar O
. O

In O
all O
AAPC B
kindreds O
, O
a O
predominance O
of O
right B
- I
sided I
colorectal I
adenomas I
and O
rectal B
polyp I
sparing O
was O
observed O
. O

No O
desmoid B
tumors I
were O
found O
in O
these O
kindreds O
. O

Our O
data O
suggest O
that O
, O
in O
AAPC B
families O
, O
the O
location O
of O
the O
APC B
mutation O
may O
partially O
predict O
specific O
phenotypic O
expression O
. O

This O
should O
help O
in O
the O
design O
of O
tailored O
clinical O
- O
management O
protocols O
in O
this O
subset O
of O
FAP B
patients O
. O
. O

Wilms B
' I
tumor I
1 O
and O
Dax O
- O
1 O
modulate O
the O
orphan O
nuclear O
receptor O
SF O
- O
1 O
in O
sex O
- O
specific O
gene O
expression O
. O

Products O
of O
steroidogenic O
factor O
1 O
( O
SF O
- O
1 O
) O
and O
Wilms B
tumor I
1 O
( O
WT1 O
) O
genes O
are O
essential O
for O
mammalian O
gonadogenesis O
prior O
to O
sexual O
differentiation O
. O

In O
males O
, O
SF O
- O
1 O
participates O
in O
sexual O
development O
by O
regulating O
expression O
of O
the O
polypeptide O
hormone O
Mullerian O
inhibiting O
substance O
( O
MIS O
) O
. O

Here O
, O
we O
show O
that O
WT1 O
- O
KTS O
isoforms O
associate O
and O
synergize O
with O
SF O
- O
1 O
to O
promote O
MIS O
expression O
. O

In O
contrast O
, O
WT1 O
missense O
mutations O
, O
associated O
with O
male O
pseudohermaphroditism I
in O
Denys B
- I
Drash I
syndrome I
, O
fail O
to O
synergize O
with O
SF O
- O
1 O
. O

Additionally O
, O
the O
X O
- O
linked O
, O
candidate O
dosage O
- O
sensitive O
sex O
- O
reversal O
gene O
, O
Dax O
- O
1 O
, O
antagonizes O
synergy O
between O
SF O
- O
1 O
and O
WT1 O
, O
most O
likely O
through O
a O
direct O
interaction O
with O
SF O
- O
1 O
. O

We O
propose O
that O
WT1 O
and O
Dax O
- O
1 O
functionally O
oppose O
each O
other O
in O
testis O
development O
by O
modulating O
SF O
- O
1 O
- O
mediated O
transactivation O
. O
. O

A O
mouse O
model O
for O
Prader B
- I
Willi I
syndrome I
imprinting O
- O
centre O
mutations O
. O

Imprinting O
in O
the O
15q11 O
- O
q13 O
region O
involves O
an O
imprinting O
centre O
( O
IC O
) O
, O
mapping O
in O
part O
to O
the O
promoter O
and O
first O
exon O
of O
SNRPN O
. O

Deletion O
of O
this O
IC O
abolishes O
local O
paternally O
derived O
gene O
expression O
and O
results O
in O
Prader B
- I
Willi I
syndrome I
( O
PWS B
) O
. O

We O
have O
created O
two O
deletion O
mutations O
in O
mice O
to O
understand O
PWS B
and O
the O
mechanism O
of O
this O
IC O
. O

Mice O
harbouring O
an O
intragenic O
deletion O
in O
Snrpn O
are O
phenotypically O
normal O
, O
suggesting O
that O
mutations O
of O
SNRPN O
are O
not O
sufficient O
to O
induce O
PWS B
. O

Mice O
with O
a O
larger O
deletion O
involving O
both O
Snrpn O
and O
the O
putative O
PWS B
- O
IC O
lack O
expression O
of O
the O
imprinted O
genes O
Zfp127 O
( O
mouse O
homologue O
of O
ZNF127 O
) O
, O
Ndn O
and O
Ipw O
, O
and O
manifest O
several O
phenotypes O
common O
to O
PWS B
infants O
. O

These O
data O
demonstrate O
that O
both O
the O
position O
of O
the O
IC O
and O
its O
role O
in O
the O
coordinate O
expression O
of O
genes O
is O
conserved O
between O
mouse O
and O
human O
, O
and O
indicate O
that O
the O
mouse O
is O
a O
suitable O
model O
system O
in O
which O
to O
investigate O
the O
molecular O
mechanisms O
of O
imprinting O
in O
this O
region O
of O
the O
genome O
. O
. O

Mutations O
of O
the O
ATM O
gene O
detected O
in O
Japanese O
ataxia B
- I
telangiectasia I
patients O
: O
possible O
preponderance O
of O
the O
two O
founder O
mutations O
4612del165 O
and O
7883del5 O
. O

The O
ATM O
( O
A B
- I
T I
, O
mutated O
) O
gene O
on O
human O
chromosome O
11q22 O
. O

3 O
has O
recently O
been O
identified O
as O
the O
gene O
responsible O
for O
the O
human O
recessive B
disease I
ataxia B
- I
telangiectasia I
( O
A B
- I
T I
) O
. O

In O
order O
to O
define O
the O
types O
of O
disease O
- O
causing O
ATM O
mutations O
in O
Japanese O
A B
- I
T I
patients O
as O
well O
as O
to O
look O
for O
possible O
mutational O
hotspots O
, O
reverse O
- O
transcribed O
RNA O
derived O
from O
ten O
patients O
belonging O
to O
eight O
unrelated O
Japanese O
A B
- I
T I
families O
was O
analyzed O
for O
mutations O
by O
the O
restriction O
endonuclease O
fingerprinting O
method O
. O

As O
has O
been O
reported O
by O
others O
, O
mutations O
that O
lead O
to O
exon O
skipping O
or O
premature O
protein O
truncation O
were O
also O
predominant O
in O
our O
mutants O
. O

Six O
different O
mutations O
were O
identified O
on O
12 O
of O
the O
16 O
alleles O
examined O
. O

Four O
were O
deletions O
involving O
a O
loss O
of O
a O
single O
exon O
exon O
7 O
, O
exon O
16 O
, O
exon O
33 O
or O
exon O
35 O
. O

The O
others O
were O
minute O
deletions O
, O
4649delA O
in O
exon O
33 O
and O
7883del5 O
in O
exon O
55 O
. O

The O
mutations O
4612del165 O
and O
7883del5 O
were O
found O
in O
more O
than O
two O
unrelated O
families O
; O
44 O
% O
( O
7 O
of O
16 O
) O
of O
the O
mutant O
alleles O
had O
one O
of O
the O
two O
mutations O
. O

The O
4612del165 O
mutations O
in O
three O
different O
families O
were O
all O
ascribed O
to O
the O
same O
T O
- O
- O
> O
A O
substitution O
at O
the O
splice O
donor O
site O
in O
intron O
33 O
. O

Microsatellite O
genotyping O
around O
the O
ATM O
locus O
also O
indicated O
that O
a O
common O
haplotype O
was O
shared O
by O
the O
mutant O
alleles O
in O
both O
mutations O
. O

This O
suggests O
that O
these O
two O
founder O
mutations O
may O
be O
predominant O
among O
Japanese O
ATM O
mutant O
alleles O
. O

W474C O
amino O
acid O
substitution O
affects O
early O
processing O
of O
the O
alpha O
- O
subunit O
of O
beta O
- O
hexosaminidase O
A O
and O
is O
associated O
with O
subacute B
G I
( I
M2 I
) I
gangliosidosis I
. O

Mutations O
in O
the O
HEXA O
gene O
, O
encoding O
the O
alpha O
- O
subunit O
of O
beta O
- O
hexosaminidase O
A O
( O
Hex O
A O
) O
, O
that O
abolish O
Hex O
A O
enzyme O
activity O
cause O
Tay B
- I
Sachs I
disease I
( O
TSD B
) O
, O
the O
fatal O
infantile O
form I
of I
G I
( I
M2 I
) I
gangliosidosis I
, I
Type I
1 I
. O

Less O
severe O
, O
subacute O
( O
juvenile O
- O
onset O
) O
and O
chronic O
( O
adult O
- O
onset O
) O
variants O
are O
characterized O
by O
a O
broad O
spectrum O
of O
clinical O
manifestations O
and O
are O
associated O
with O
residual O
levels O
of O
Hex O
A O
enzyme O
activity O
. O

We O
identified O
a O
1422 O
G O
- O
- O
> O
C O
( O
amino O
acid O
W474C O
) O
substitution O
in O
the O
first O
position O
of O
exon O
13 O
of O
HEXA O
of O
a O
non O
- O
Jewish O
proband O
who O
manifested O
a O
subacute O
variant O
of O
G B
( I
M2 I
) I
gangliosidosis I
. O

On O
the O
second O
maternally O
inherited O
allele O
, O
we O
identified O
the O
common O
infantile O
disease I
- O
causing O
4 O
- O
bp O
insertion O
, O
+ O
TATC O
1278 O
, O
in O
exon O
11 O
. O

Pulse O
- O
chase O
analysis O
using O
proband O
fibroblasts O
revealed O
that O
the O
W474C O
- O
containing O
alpha O
- O
subunit O
precursor O
was O
normally O
synthesized O
, O
but O
not O
phosphorylated O
or O
secreted O
, O
and O
the O
mature O
lysosomal O
alpha O
- O
subunit O
was O
not O
detected O
. O

When O
the O
W474C O
- O
containing O
alpha O
- O
subunit O
was O
transiently O
co O
- O
expressed O
with O
the O
beta O
- O
subunit O
to O
produce O
Hex O
A O
( O
alphabeta O
) O
in O
COS O
- O
7 O
cells O
, O
the O
mature O
alpha O
- O
subunit O
was O
present O
, O
but O
its O
level O
was O
much O
lower O
than O
that O
from O
normal O
alpha O
- O
subunit O
transfections O
, O
although O
higher O
than O
in O
those O
cells O
transfected O
with O
an O
alpha O
- O
subunit O
associated O
with O
infantile O
TSD B
. O

Furthermore O
, O
the O
precursor O
level O
of O
the O
W474C O
alpha O
- O
subunit O
was O
found O
to O
accumulate O
in O
comparison O
to O
the O
normal O
alpha O
- O
subunit O
precursor O
levels O
. O

We O
conclude O
that O
the O
1422 O
G O
- O
- O
> O
C O
mutation O
is O
the O
cause O
of O
Hex O
A O
enzyme I
deficiency I
in O
the O
proband O
. O

The O
resulting O
W474C O
substitution O
clearly O
interferes O
with O
alpha O
- O
subunit O
processing O
, O
but O
because O
the O
base O
substitution O
falls O
at O
the O
first O
position O
of O
exon O
13 O
, O
aberrant O
splicing O
may O
also O
contribute O
to O
Hex B
A I
deficiency I
in O
this O
proband O
. O
. O

Two O
frequent O
missense O
mutations O
in O
Pendred B
syndrome I
. O

Pendred B
syndrome I
is O
an O
autosomal B
recessive I
disorder I
characterized O
by O
early O
childhood O
deafness B
and O
goiter B
. O

A O
century O
after O
its O
recognition O
as O
a O
syndrome O
by O
Vaughan O
Pendred O
, O
the O
disease O
gene O
( O
PDS B
) O
was O
mapped O
to O
chromosome O
7q22 O
- O
q31 O
. O

1 O
and O
, O
recently O
, O
found O
to O
encode O
a O
putative O
sulfate O
transporter O
. O

We O
performed O
mutation O
analysis O
of O
the O
PDS B
gene O
in O
patients O
from O
14 O
Pendred O
families O
originating O
from O
seven O
countries O
and O
identified O
all O
mutations O
. O

The O
mutations O
include O
three O
single O
base O
deletions O
, O
one O
splice O
site O
mutation O
and O
10 O
missense O
mutations O
. O

One O
missense O
mutation O
( O
L236P O
) O
was O
found O
in O
a O
homozygous O
state O
in O
two O
consanguineous O
families O
and O
in O
a O
heterozygous O
state O
in O
five O
additional O
non O
- O
consanguineous O
families O
. O

Another O
missense O
mutation O
( O
T416P O
) O
was O
found O
in O
a O
homozygous O
state O
in O
one O
family O
and O
in O
a O
heterozygous O
state O
in O
four O
families O
. O

Pendred O
patients O
in O
three O
non O
- O
consanguineous O
families O
were O
shown O
to O
be O
compound O
heterozygotes O
for O
L236P O
and O
T416P O
. O

In O
total O
, O
one O
or O
both O
of O
these O
mutations O
were O
found O
in O
nine O
of O
the O
14 O
families O
analyzed O
. O

The O
identification O
of O
two O
frequent O
PDS B
mutations O
will O
facilitate O
the O
molecular O
diagnosis O
of O
Pendred B
syndrome I
. O

Insertional O
mutation O
by O
transposable O
element O
, O
L1 O
, O
in O
the O
DMD B
gene O
results O
in O
X B
- I
linked I
dilated I
cardiomyopathy I
. O

X B
- I
linked I
dilated I
cardiomyopathy I
( O
XLDCM B
) O
is O
a O
clinical O
phenotype O
of O
dystrophinopathy B
which O
is O
characterized O
by O
preferential O
myocardial B
involvement I
without O
any O
overt O
clinical O
signs O
of O
skeletal B
myopathy I
. O

To O
date O
, O
several O
mutations O
in O
the O
Duchenne B
muscular I
dystrophy I
gene O
, O
DMD B
, O
have O
been O
identified O
in O
patients O
with O
XLDCM B
, O
but O
a O
pathogenic O
correlation O
of O
these O
cardiospecific O
mutations O
in O
DMD B
with O
the O
XLDCM B
phenotype O
has O
remained O
to O
be O
elucidated O
. O

We O
report O
here O
the O
identification O
of O
a O
unique O
de O
novo O
L1 O
insertion O
in O
the O
muscle O
exon O
1 O
in O
DMD B
in O
three O
XLDCM B
patients O
from O
two O
unrelated O
Japanese O
families O
. O

The O
insertion O
was O
a O
5 O
- O
truncated O
form O
of O
human O
L1 O
inversely O
integrated O
in O
the O
5 O
- O
untranslated O
region O
in O
the O
muscle O
exon O
1 O
, O
which O
affected O
the O
transcription O
or O
the O
stability O
of O
the O
muscle O
form O
of O
dystrophin O
transcripts O
but O
not O
that O
of O
the O
brain O
or O
Purkinje O
cell O
form O
, O
probably O
due O
to O
its O
unique O
site O
of O
integration O
. O

We O
speculate O
that O
this O
insertion O
of O
an O
L1 O
sequence O
in O
DMD B
is O
responsible O
for O
some O
of O
the O
population O
of O
Japanese O
patients O
with O
XLDCM B
. O
. O

Severe O
early O
- O
onset O
obesity B
, O
adrenal B
insufficiency I
and O
red B
hair I
pigmentation I
caused O
by O
POMC O
mutations O
in O
humans O
. O

Sequential O
cleavage O
of O
the O
precursor O
protein O
pre O
- O
pro O
- O
opiomelanocortin O
( O
POMC O
) O
generates O
the O
melanocortin O
peptides O
adrenocorticotrophin O
( O
ACTH O
) O
, O
melanocyte O
- O
stimulating O
hormones O
( O
MSH O
) O
alpha O
, O
beta O
and O
gamma O
as O
well O
as O
the O
opioid O
- O
receptor O
ligand O
beta O
- O
endorphin O
. O

While O
a O
few O
cases O
of O
isolated O
ACTH I
deficiency I
have O
been O
reported O
( O
OMIM O
201400 O
) O
, O
an O
inherited O
POMC I
defect I
has O
not O
been O
described O
so O
far O
. O

Recent O
studies O
in O
animal O
models O
elucidated O
a O
central O
role O
of O
alpha O
- O
MSH O
in O
the O
regulation O
of O
food O
intake O
by O
activation O
of O
the O
brain O
melanocortin O
- O
4 O
- O
receptor O
( O
MC4 O
- O
R O
; O
refs O
3 O
- O
5 O
) O
and O
the O
linkage O
of O
human O
obesity B
to O
chromosome O
2 O
in O
close O
proximity O
to O
the O
POMC O
locus O
, O
led O
to O
the O
proposal O
of O
an O
association O
of O
POMC O
with O
human O
obesity B
. O

The O
dual O
role O
of O
alpha O
- O
MSH O
in O
regulating O
food O
intake O
and O
influencing O
hair O
pigmentation O
predicts O
that O
the O
phenotype O
associated O
with O
a O
defect O
in O
POMC O
function O
would O
include O
obesity B
, O
alteration O
in O
pigmentation O
and O
ACTH B
deficiency I
. O

The O
observation O
of O
these O
symptoms O
in O
two O
probands O
prompted O
us O
to O
search O
for O
mutations O
within O
their O
POMC O
genes O
. O

Patient O
1 O
was O
found O
to O
be O
a O
compound O
heterozygote O
for O
two O
mutations O
in O
exon O
3 O
( O
G7013T O
, O
C7133delta O
) O
which O
interfere O
with O
appropriate O
synthesis O
of O
ACTH O
and O
alpha O
- O
MSH O
. O

Patient O
2 O
was O
homozygous O
for O
a O
mutation O
in O
exon O
2 O
( O
C3804A O
) O
which O
abolishes O
POMC O
translation O
. O

These O
findings O
represent O
the O
first O
examples O
of O
a O
genetic B
defect I
within O
the O
POMC O
gene O
and O
define O
a O
new O
monogenic B
endocrine I
disorder I
resulting O
in O
early O
- O
onset O
obesity B
, O
adrenal B
insufficiency I
and O
red B
hair I
pigmentation I
. O
. O

A O
European O
multicenter O
study O
of O
phenylalanine B
hydroxylase I
deficiency I
: O
classification O
of O
105 O
mutations O
and O
a O
general O
system O
for O
genotype O
- O
based O
prediction O
of O
metabolic O
phenotype O
. O

Phenylketonuria B
( O
PKU B
) O
and O
mild O
hyperphenylalaninemia B
( O
MHP B
) O
are O
allelic B
disorders I
caused O
by O
mutations O
in O
the O
gene O
encoding O
phenylalanine O
hydroxylase O
( O
PAH O
) O
. O

Previous O
studies O
have O
suggested O
that O
the O
highly O
variable O
metabolic O
phenotypes O
of O
PAH B
deficiency I
correlate O
with O
PAH O
genotypes O
. O

We O
identified O
both O
causative O
mutations O
in O
686 O
patients O
from O
seven O
European O
centers O
. O

On O
the O
basis O
of O
the O
phenotypic O
characteristics O
of O
297 O
functionally O
hemizygous O
patients O
, O
105 O
of O
the O
mutations O
were O
assigned O
to O
one O
of O
four O
arbitrary O
phenotype O
categories O
. O

We O
proposed O
and O
tested O
a O
simple O
model O
for O
correlation O
between O
genotype O
and O
phenotypic O
outcome O
. O

The O
observed O
phenotype O
matched O
the O
predicted O
phenotype O
in O
79 O
% O
of O
the O
cases O
, O
and O
in O
only O
5 O
of O
184 O
patients O
was O
the O
observed O
phenotype O
more O
than O
one O
category O
away O
from O
that O
expected O
. O

Among O
the O
seven O
contributing O
centers O
, O
the O
proportion O
of O
patients O
for O
whom O
the O
observed O
phenotype O
did O
not O
match O
the O
predicted O
phenotype O
was O
4 O
% O
- O
23 O
% O
( O
P O
< O
. O
0001 O
) O
, O
suggesting O
that O
differences O
in O
methods O
used O
for O
mutation O
detection O
or O
phenotype O
classification O
may O
account O
for O
a O
considerable O
proportion O
of O
genotype O
- O
phenotype O
inconsistencies O
. O

Our O
data O
indicate O
that O
the O
PAH O
- O
mutation O
genotype O
is O
the O
main O
determinant O
of O
metabolic O
phenotype O
in O
most O
patients O
with O
PAH B
deficiency I
. O

In O
the O
present O
study O
, O
the O
classification O
of O
105 O
PAH O
mutations O
may O
allow O
the O
prediction O
of O
the O
biochemical O
phenotype O
in O
> O
10 O
, O
000 O
genotypes O
, O
which O
may O
be O
useful O
for O
the O
management O
of O
hyperphenylalaninemia B
in O
newborns O
. O

Somatic O
instability O
of O
the O
CTG O
repeat O
in O
mice O
transgenic O
for O
the O
myotonic B
dystrophy I
region O
is O
age O
dependent O
but O
not O
correlated O
to O
the O
relative O
intertissue O
transcription O
levels O
and O
proliferative O
capacities O
. O

A O
( O
CTG O
) O
nexpansion O
in O
the O
3 O
- O
untranslated O
region O
( O
UTR O
) O
of O
the O
DM B
protein O
kinase O
gene O
( O
DMPK O
) O
is O
responsible O
for O
causing O
myotonic B
dystrophy I
( O
DM B
) O
. O

Major O
instability O
, O
with O
very O
large O
expansions O
between O
generations O
and O
high O
levels O
of O
somatic O
mosaicism O
, O
is O
observed O
in O
patients O
. O

There O
is O
a O
good O
correlation O
between O
repeat O
size O
( O
at O
least O
in O
leucocytes O
) O
, O
clinical O
severity O
and O
age O
of O
onset O
. O

The O
trinucleotide O
repeat O
instability O
mechanisms O
involved O
in O
DM B
and O
other O
human O
genetic B
diseases I
are O
unknown O
. O

We O
studied O
somatic O
instability O
by O
measuring O
the O
CTG O
repeat O
length O
at O
several O
ages O
in O
various O
tissues O
of O
transgenic O
mice O
carrying O
a O
( O
CTG O
) O
55expansion O
surrounded O
by O
45 O
kb O
of O
the O
human O
DM B
region O
, O
using O
small O
- O
pool O
PCR O
. O

These O
mice O
have O
been O
shown O
to O
reproduce O
the O
intergenerational O
and O
somatic O
instability O
of O
the O
55 O
CTG O
repeat O
suggesting O
that O
surrounding O
sequences O
and O
the O
chromatin O
environment O
are O
involved O
in O
instability O
mechanisms O
. O

As O
observed O
in O
some O
of O
the O
tissues O
of O
DM B
patients O
, O
there O
is O
a O
tendency O
for O
repeat O
length O
and O
somatic O
mosaicism O
to O
increase O
with O
the O
age O
of O
the O
mouse O
. O

Furthermore O
, O
we O
observed O
no O
correlation O
between O
the O
somatic O
mutation O
rate O
and O
tissue O
proliferation O
capacity O
. O

The O
somatic O
mutation O
rates O
in O
different O
tissues O
were O
also O
not O
correlated O
to O
the O
relative O
inter O
- O
tissue O
difference O
in O
transcriptional O
levels O
of O
the O
three O
genes O
( O
DMAHP O
, O
DMPK O
and O
59 O
) O
surrounding O
the O
repeat O
. O
. O

A O
novel O
missense O
mutation O
in O
patients O
from O
a O
retinoblastoma B
pedigree O
showing O
only O
mild O
expression O
of O
the O
tumor B
phenotype O
. O

We O
have O
used O
single O
strand O
conformation O
polymorphism O
analysis O
to O
study O
the O
27 O
exons O
of O
the O
RB1 O
gene O
in O
individuals O
from O
a O
family O
showing O
mild O
expression O
of O
the O
retinoblastoma B
phenotype O
. O

In O
this O
family O
affected O
individuals O
developed O
unilateral B
tumors I
and O
, O
as O
a O
result O
of O
linkage O
analysis O
, O
unaffected O
mutation O
carriers O
were O
also O
identified O
within O
the O
pedigree O
. O

A O
single O
band O
shift O
using O
SSCP O
was O
identified O
in O
exon O
21 O
which O
resulted O
in O
a O
missense O
mutation O
converting O
a O
cys O
- O
- O
> O
arg O
at O
nucleotide O
position O
28 O
in O
the O
exon O
. O

The O
mutation O
destroyed O
an O
NdeI O
restriction O
enzyme O
site O
. O

Analysis O
of O
all O
family O
members O
demonstrated O
that O
the O
missense O
mutation O
co O
- O
segregated O
with O
patients O
with O
tumors B
or O
who O
, O
as O
a O
result O
of O
linkage O
analysis O
had O
been O
predicted O
to O
carry O
the O
predisposing O
mutation O
. O

These O
observations O
point O
to O
another O
region O
of O
the O
RB1 O
gene O
where O
mutations O
only O
modify O
the O
function O
of O
the O
gene O
and O
raise O
important O
questions O
for O
genetic O
counseling O
in O
families O
with O
these O
distinctive O
phenotypes O
. O
. O

Maternal B
disomy I
and O
Prader B
- I
Willi I
syndrome I
consistent O
with O
gamete O
complementation O
in O
a O
case O
of O
familial O
translocation O
( O
3 O
; O
15 O
) O
( O
p25 O
; O
q11 O
. O
2 O
) O
. O

Maternal B
uniparental I
disomy I
( O
UPD B
) O
for I
chromosome I
15 I
is O
responsible O
for O
an O
estimated O
30 O
% O
of O
cases O
of O
Prader B
- I
Willi I
syndrome I
( O
PWS B
) O
. O

We O
report O
on O
an O
unusual O
case O
of O
maternal B
disomy I
15 I
in O
PWS B
that O
is O
most O
consistent O
with O
adjacent O
- O
1 O
segregation O
of O
a O
paternal O
t O
( O
3 O
; O
15 O
) O
( O
p25 O
; O
q11 O
. O
2 O
) O
with O
simultaneous O
maternal O
meiotic O
nondisjunction O
for O
chromosome O
15 O
. O

The O
patient O
( O
J O
. O
B O
. O
) O
, O
a O
17 O
- O
year O
- O
old O
white O
male O
with O
PWS B
, O
was O
found O
to O
have O
47 O
chromosomes O
with O
a O
supernumerary O
, O
paternal O
der O
( O
15 O
) O
consisting O
of O
the O
short O
arm O
and O
the O
proximal O
long O
arm O
of O
chromosome O
15 O
, O
and O
distal O
chromosome O
arm O
3p O
. O

The O
t O
( O
3 O
; O
15 O
) O
was O
present O
in O
the O
balanced O
state O
in O
the O
patients O
father O
and O
a O
sister O
. O

Fluorescent O
in O
situ O
hybridization O
analysis O
demonstrated O
that O
the O
PWS B
critical O
region O
resided O
on O
the O
derivative O
chromosome O
3 O
and O
that O
there O
was O
no O
deletion O
of O
the O
PWS B
region O
on O
the O
normal O
pair O
of O
15s O
present O
in O
J O
. O

B O
. O

Methylation O
analysis O
at O
exon O
alpha O
of O
the O
small O
nuclear O
ribonucleoprotein O
- O
associated O
polypeptide O
N O
( O
SNRPN O
) O
gene O
showed O
a O
pattern O
characteristic O
of O
only O
the O
maternal O
chromosome O
15 O
in O
J O
. O

B O
. O

Maternal B
disomy I
was O
confirmed O
by O
polymerase O
chain O
reaction O
analysis O
of O
microsatellite O
repeats O
at O
the O
gamma O
- O
aminobutyric O
acid O
receptor O
beta3 O
subunit O
( O
GABRB3 O
) O
locus O
. O

A O
niece O
( O
B O
. O
B O
. O
) O
with O
45 O
chromosomes O
and O
the O
derivative O
3 O
but O
without O
the O
der O
( O
15 O
) O
demonstrated O
a O
phenotype O
consistent O
with O
that O
reported O
for O
haploinsufficiency B
of I
distal I
3 I
p I
. O

Uniparental B
disomy I
associated O
with O
unbalanced O
segregation O
of O
non O
- O
Robertsonian O
translocations O
has O
been O
reported O
previously O
but O
has O
not O
, O
to O
our O
knowledge O
, O
been O
observed O
in O
a O
case O
of O
PWS B
. O

Furthermore O
, O
our O
findings O
are O
best O
interpreted O
as O
true O
gamete O
complementation O
resulting O
in O
maternal O
UPD O
15 O
and O
PWS B

Schwartz B
- I
Jampel I
syndrome I
type I
2 I
and O
Stuve B
- I
Wiedemann I
syndrome I
: O
a O
case O
for O
" O
lumping O
" O
. O

Recent O
studies O
demonstrated O
the O
existence O
of O
a O
genetically O
distinct O
, O
usually O
lethal O
form O
of O
the O
Schwartz B
- I
Jampel I
syndrome I
( O
SJS B
) O
of O
myotonia B
and O
skeletal B
dysplasia I
, O
which O
we O
called O
SJS B
type I
2 I
. O

This O
disorder O
is O
reminiscent O
of O
another O
rare O
condition O
, O
the O
Stuve B
- I
Wiedemann I
syndrome I
( O
SWS B
) O
, O
which O
comprises O
campomelia B
at O
birth O
with O
skeletal B
dysplasia I
, O
contractures B
, O
and O
early O
death O
. O

To O
test O
for O
possible O
nosologic O
identity O
between O
these O
disorders O
, O
we O
reviewed O
the O
literature O
and O
obtained O
a O
follow O
- O
up O
of O
the O
only O
two O
surviving O
patients O
, O
one O
with O
SJS B
type I
2 I
at O
age O
10 O
years O
and O
another O
with O
SWS B
at O
age O
7 O
years O
. O

Patients O
reported O
as O
having O
either O
neonatal B
SJS I
or O
SWS B
presented O
a O
combination O
of O
a O
severe O
, O
prenatal O
- O
onset O
neuromuscular B
disorder I
( O
with O
congenital B
joint I
contractures I
, O
respiratory O
and O
feeding O
difficulties O
, O
tendency O
to O
hyperthermia B
, O
and O
frequent O
death O
in O
infancy O
) O
with O
a O
distinct O
campomelic B
- I
metaphyseal I
skeletal I
dysplasia I
. O

The O
similarity O
of O
the O
clinical O
and O
radiographic O
findings O
is O
so O
extensive O
that O
these O
disorders O
appear O
to O
be O
a O
single O
entity O
. O

The O
follow O
- O
up O
observation O
of O
an O
identical O
and O
unique O
pattern O
of O
progressive O
bone B
dysplasia I
in O
the O
two O
patients O
( O
one O
with O
SJS B
type I
2 I
, O
one O
with O
SWS B
) O
surviving O
beyond O
infancy O
adds O
to O
the O
evidence O
in O
favor O
of O
identity O
. O

The O
hypothesis O
that O
SWS B
and O
SJS B
type I
2 I
are O
the O
same O
disorder O
should O
be O
testable O
by O
molecular O
methods O
. O
. O

A O
mouse O
model O
of O
severe B
von I
Willebrand I
disease I
: O
defects O
in O
hemostasis B
and O
thrombosis B
. O

von B
Willebrand I
factor I
( I
vWf I
) I
deficiency I
causes O
severe O
von B
Willebrand I
disease I
in O
humans O
. O

We O
generated O
a O
mouse O
model O
for O
this O
disease O
by O
using O
gene O
targeting O
. O

vWf B
- O
deficient I
mice O
appeared O
normal O
at O
birth O
; O
they O
were O
viable O
and O
fertile O
. O

Neither O
vWf O
nor O
vWf O
propolypeptide O
( O
von B
Willebrand I
antigen O
II O
) O
were O
detectable O
in O
plasma O
, O
platelets O
, O
or O
endothelial O
cells O
of O
the O
homozygous O
mutant O
mice O
. O

The O
mutant O
mice O
exhibited O
defects O
in O
hemostasis O
with O
a O
highly O
prolonged O
bleeding O
time O
and O
spontaneous O
bleeding O
events O
in O
approximately O
10 O
% O
of O
neonates O
. O

As O
in O
the O
human O
disease O
, O
the O
factor O
VIII O
level O
in O
these O
mice O
was O
reduced O
strongly O
as O
a O
result O
of O
the O
lack O
of O
protection O
provided O
by O
vWf O
. O

Defective O
thrombosis I
in O
mutant O
mice O
was O
also O
evident O
in O
an O
in O
vivo O
model O
of O
vascular B
injury I
. O

In O
this O
model O
, O
the O
exteriorized O
mesentery O
was O
superfused O
with O
ferric O
chloride O
and O
the O
accumulation O
of O
fluorescently O
labeled O
platelets O
was O
observed O
by O
intravital O
microscopy O
. O

We O
conclude O
that O
these O
mice O
very O
closely O
mimic O
severe O
human O
von B
Willebrand I
disease I
and O
will O
be O
very O
useful O
for O
investigating O
the O
role O
of O
vWf O
in O
normal O
physiology O
and O
in O
disease O
models O
. O
. O

Oral O
contraceptives O
and O
the O
risk O
of O
hereditary B
ovarian I
cancer I
. O

Hereditary B
Ovarian I
Cancer I
Clinical O
Study O
Group O
. O

BACKGROUND O
Women O
with O
mutations O
in O
either O
the O
BRCA1 O
or O
the O
BRCA2 O
gene O
have O
a O
high O
lifetime O
risk O
of O
ovarian B
cancer I
. O

Oral O
contraceptives O
protect O
against O
ovarian B
cancer I
in O
general O
, O
but O
it O
is O
not O
known O
whether O
they O
also O
protect O
against O
hereditary O
forms O
of I
ovarian I
cancer I
. O

METHODS O
We O
enrolled O
207 O
women O
with O
hereditary B
ovarian I
cancer I
and O
161 O
of O
their O
sisters O
as O
controls O
in O
a O
case O
- O
control O
study O
. O

All O
the O
patients O
carried O
a O
pathogenic O
mutation O
in O
either O
BRCA1 O
( O
179 O
women O
) O
or O
BRCA2 O
( O
28 O
women O
) O
. O

The O
control O
women O
were O
enrolled O
regardless O
of O
whether O
or O
not O
they O
had O
either O
mutation O
. O

Lifetime O
histories O
of O
oral O
- O
contraceptive O
use O
were O
obtained O
by O
interview O
or O
by O
written O
questionnaire O
and O
were O
compared O
between O
patients O
and O
control O
women O
, O
after O
adjustment O
for O
year O
of O
birth O
and O
parity O
. O

RESULTS O
The O
adjusted O
odds O
ratio O
for O
ovarian B
cancer I
associated O
with O
any O
past O
use O
of O
oral O
contraceptives O
was O
0 O
. O

5 O
( O
95 O
percent O
confidence O
interval O
, O
0 O
. O
3 O
to O
0 O
. O
8 O
) O
. O

The O
risk O
decreased O
with O
increasing O
duration O
of O
use O
( O
P O
for O
trend O
, O
< O
0 O
. O
001 O
) O
; O
use O
for O
six O
or O
more O
years O
was O
associated O
with O
a O
60 O
percent O
reduction O
in O
risk O
. O

Oral O
- O
contraceptive O
use O
protected O
against O
ovarian B
cancer I
both O
for O
carriers O
of O
the O
BRCA1 O
mutation O
( O
odds O
ratio O
, O
0 O
. O
5 O
; O
95 O
percent O
confidence O
interval O
, O
0 O
. O
3 O
to O
0 O
. O
9 O
) O
and O
for O
carriers O
of O
the O
BRCA2 O
mutation O
( O
odds O
ratio O
, O
0 O
. O
4 O
; O
95 O
percent O
confidence O
interval O
, O
0 O
. O
2 O
to O
1 O
. O
1 O
) O
. O

CONCLUSIONS O
Oral O
- O
contraceptive O
use O
may O
reduce O
the O
risk O
of O
ovarian B
cancer I
in O
women O
with O
pathogenic O
mutations O
in O
the O
BRCA1 O
or O
BRCA2 O
gene O

A O
Japanese O
family O
with O
adrenoleukodystrophy B
with O
a O
codon O
291 O
deletion O
: O
a O
clinical O
, O
biochemical O
, O
pathological O
, O
and O
genetic O
report O
. O

We O
report O
a O
Japanese O
family O
with O
adrenoleukodystrophy B
( O
ALD B
) O
with O
a O
three O
base O
pair O
deletion O
( O
delGAG O
291 O
) O
in O
the O
ALD B
gene O
. O

A O
variety O
of O
phenotypes O
were O
observed O
within O
this O
family O
. O

While O
the O
proband O
( O
patient O
1 O
) O
was O
classified O
as O
having O
a O
rare O
intermediate O
type O
of O
adult O
cerebral O
and O
cerebello O
- O
brain O
stem O
forms O
, O
his O
younger O
brother O
( O
patient O
2 O
) O
and O
nephew O
( O
patient O
3 O
) O
had O
a O
childhood O
ALD B
type O
. O

Another O
nephew O
( O
patient O
4 O
) O
of O
patient O
1 O
was O
classified O
as O
having O
an O
adolescent O
form O
. O

The O
tau O
level O
in O
the O
cerebrospinal O
fluid O
( O
CSF O
) O
in O
patient O
1 O
was O
as O
high O
as O
that O
of O
patients O
with O
Alzheimers B
disease I
( O
AD B
) O
. O

His O
brain O
magnetic O
resonance O
image O
( O
MRI O
) O
showed O
abnormalities O
in O
the O
bilateral O
cerebellar O
hemispheres O
and O
brain O
stem O
, O
but O
not O
in O
the O
cerebral O
white O
matter O
, O
where O
marked O
reductions O
of O
the O
cerebral O
blood O
flow O
and O
oxygen O
metabolism O
were O
clearly O
demonstrated O
by O
positron O
emission O
tomography O
( O
PET O
) O
. O

In O
patients O
2 O
and O
3 O
, O
the O
autopsy O
findings O
showed O
massive O
demyelination B
of I
the I
cerebral I
white I
matter I
with O
sparing O
of O
the O
U O
- O
fibers O
, O
compatible O
with O
the O
findings O
of O
childhood O
ALD B
. O

Oleic O
and O
erucic O
acids O
( O
Lorenzos O
Oil O
) O
were O
administered O
to O
patients O
1 O
and O
4 O
, O
but O
sufficient O
effectiveness O
was O
not O
obtained O
. O

The O
findings O
in O
this O
family O
suggest O
that O
delGAG291 O
is O
part O
of O
the O
cause O
of O
Japanese O
ALD B
with O
phenotypic O
variations O
. O

Moreover O
, O
although O
the O
scale O
of O
the O
study O
is O
limited O
, O
there O
is O
a O
possibility O
that O
PET O
can O
detect O
an O
insidious O
lesion O
which O
is O
undetectable O
by O
computed O
tomogram O
( O
CT O
) O
or O
MRI O
analysis O
, O
and O
that O
the O
higher O
level O
of O
tau O
reflects O
the O
process O
of O
neuronal B
degeneration I
in O
ALD B
. O

Lorenzos O
Oil O
should O
be O
given O
in O
the O
early O
stage O
. O
. O

Nonsense O
mutation O
in O
exon O
4 O
of O
human O
complement O
C9 O
gene O
is O
the O
major O
cause O
of O
Japanese O
complement B
C9 I
deficiency I
. O

Deficiency B
of I
the I
ninth I
component I
of I
human I
complement I
( O
C9 O
) O
is O
the O
most O
common O
complement B
deficiency I
in O
Japan O
but O
is O
rare O
in O
other O
countries O
. O

We O
studied O
the O
molecular O
basis O
of O
C9 B
deficiency I
in O
four O
Japanese O
C9 B
- I
deficient I
patients O
who O
had O
suffered O
from O
meningococcal B
meningitis I
. O

Direct O
sequencing O
of O
amplified O
C9 O
cDNA O
and O
DNA O
revealed O
a O
nonsense O
substitution O
( O
CGA O
- O
- O
> O
TGA O
) O
at O
codon O
95 O
in O
exon O
4 O
in O
the O
four O
C9 B
- I
deficient I
individuals O
. O

An O
allele O
- O
specific O
polymerase O
chain O
reaction O
system O
designed O
to O
detect O
exclusively O
only O
one O
of O
the O
normal O
and O
mutant O
alleles O
indicated O
that O
all O
the O
four O
patients O
were O
homozygous O
for O
the O
mutation O
in O
exon O
4 O
and O
that O
the O
parents O
of O
patient O
2 O
were O
heterozygous O
. O

The O
common O
mutation O
at O
codon O
95 O
in O
exon O
4 O
might O
be O
responsible O
for O
most O
Japanese O
C9 B
deficiency I
. O
. O

BRCA1 O
required O
for O
transcription O
- O
coupled O
repair O
of O
oxidative O
DNA O
damage O
. O

The O
breast B
and I
ovarian I
cancer I
susceptibility O
gene O
BRCA1 O
encodes O
a O
zinc O
finger O
protein O
of O
unknown O
function O
. O

Association O
of O
the O
BRCA1 O
protein O
with O
the O
DNA O
repair O
protein O
Rad51 O
and O
changes O
in O
the O
phosphorylation O
and O
cellular O
localization O
of O
the O
protein O
after O
exposure O
to O
DNA O
- O
damaging O
agents O
are O
consistent O
with O
a O
role O
for O
BRCA1 O
in O
DNA O
repair O
. O

Here O
, O
it O
is O
shown O
that O
mouse O
embryonic O
stem O
cells O
deficient O
in O
BRCA1 O
are O
defective O
in O
the O
ability O
to O
carry O
out O
transcription O
- O
coupled O
repair O
of O
oxidative O
DNA O
damage O
, O
and O
are O
hypersensitive O
to O
ionizing O
radiation O
and O
hydrogen O
peroxide O
. O

These O
results O
suggest O
that O
BRCA1 O
participates O
, O
directly O
or O
indirectly O
, O
in O
transcription O
- O
coupled O
repair O
of O
oxidative O
DNA O
damage O
. O
. O

Truncation O
mutations O
in O
the O
transactivation O
region O
of O
PAX6 O
result O
in O
dominant O
- O
negative O
mutants O
. O

PAX6 O
is O
a O
transcription O
factor O
with O
two O
DNA O
- O
binding O
domains O
( O
paired O
box O
and O
homeobox O
) O
and O
a O
proline O
- O
serine O
- O
threonine O
( O
PST O
) O
- O
rich O
transactivation O
domain O
. O

PAX6 O
regulates O
eye O
development O
in O
animals O
ranging O
from O
jellyfish O
to O
Drosophila O
to O
humans O
. O

Heterozygous O
mutations O
in O
the O
human O
PAX6 O
gene O
result O
in O
various O
phenotypes O
, O
including O
aniridia B
, O
Peters B
anomaly I
, O
autosomal B
dominant I
keratitis I
, O
and O
familial B
foveal I
dysplasia I
. O

It O
is O
believed O
that O
the O
mutated O
allele O
of O
PAX6 O
produces O
an O
inactive O
protein O
and O
aniridia B
is O
caused O
due O
to O
genetic O
haploinsufficiency I
. O

However O
, O
several O
truncation O
mutations O
have O
been O
found O
to O
occur O
in O
the O
C O
- O
terminal O
half O
of O
PAX6 O
in O
patients O
with O
Aniridia B
resulting O
in O
mutant O
proteins O
that O
retain O
the O
DNA O
- O
binding O
domains O
but O
have O
lost O
most O
of O
the O
transactivation O
domain O
. O

It O
is O
not O
clear O
whether O
such O
mutants O
really O
behave O
as O
loss O
- O
of O
- O
function O
mutants O
as O
predicted O
by O
haploinsufficiency B
. O

Contrary O
to O
this O
theory O
, O
our O
data O
showed O
that O
these O
mutants O
are O
dominant O
- O
negative O
in O
transient O
transfection O
assays O
when O
they O
are O
coexpressed O
with O
wild O
- O
type O
PAX6 O
. O

We O
found O
that O
the O
dominant O
- O
negative O
effects O
result O
from O
the O
enhanced O
DNA O
binding O
ability O
of O
these O
mutants O
. O

Kinetic O
studies O
of O
binding O
and O
dissociation O
revealed O
that O
various O
truncation O
mutants O
have O
3 O
- O
5 O
- O
fold O
higher O
affinity O
to O
various O
DNA O
- O
binding O
sites O
when O
compared O
with O
the O
wild O
- O
type O
PAX6 O
. O

These O
results O
provide O
a O
new O
insight O
into O
the O
role O
of O
mutant O
PAX6 O
in O
causing O
aniridia B
. O
. O

Reversal O
of O
severe O
hypertrophic B
cardiomyopathy I
and O
excellent O
neuropsychologic O
outcome O
in O
very B
- I
long I
- I
chain I
acyl I
- I
coenzyme I
A I
dehydrogenase I
deficiency I
. O

Very B
- I
long I
- I
chain I
acyl I
- I
coenzyme I
A I
dehydrogenase I
( I
VLCAD I
) I
deficiency I
is O
a O
disorder O
of O
fatty O
acid O
beta O
oxidation O
that O
reportedly O
has O
high O
rates O
of O
morbidity O
and O
mortality O
. O

We O
describe O
the O
outcome O
of O
a O
5 O
- O
year O
- O
old O
girl O
with O
VLCAD B
deficiency I
who O
was O
first O
seen O
at O
5 O
months O
of O
age O
with O
severe O
hypertrophic B
cardiomyopathy I
, O
hepatomegaly B
, O
encephalopathy B
, O
and O
hypotonia B
. O

Biochemical O
studies O
indicated O
VLCAD B
deficiency I
caused O
by O
a O
stable O
yet O
inactive O
enzyme O
. O

Molecular O
genetic O
analysis O
of O
her O
VLCAD O
gene O
revealed O
a O
T1372C O
( O
F458L O
) O
missense O
mutation O
and O
a O
1668 O
ACAG O
1669 O
splice O
site O
mutation O
. O

After O
initial O
treatment O
with O
intravenous O
glucose O
and O
carnitine O
, O
the O
patient O
has O
thrived O
on O
a O
low O
- O
fat O
diet O
supplemented O
with O
medium O
- O
chain O
triglyceride O
oil O
and O
carnitine O
and O
avoidance O
of O
fasting O
. O

Her O
ventricular B
hypertrophy I
resolved O
significantly O
over O
1 O
year O
, O
and O
cognitively O
, O
she O
is O
in O
the O
superior O
range O
for O
age O
. O

Clinical O
recognition O
of O
VLCAD B
deficiency I
is O
important O
because O
it O
is O
one O
of O
the O
few O
directly O
treatable O
causes O
of O
cardiomyopathy B
in O
children O
. O
. O

Cloning O
of O
a O
novel O
member O
of O
the O
low O
- O
density O
lipoprotein O
receptor O
family O
. O

A O
gene O
encoding O
a O
novel O
transmembrane O
protein O
was O
identified O
by O
DNA O
sequence O
analysis O
within O
the O
insulin B
- I
dependent I
diabetes I
mellitus I
( O
IDDM B
) O
locus O
IDDM4 O
on O
chromosome O
11q13 O
. O

Based O
on O
its O
chromosomal O
position O
, O
this O
gene O
is O
a O
candidate O
for O
conferring O
susceptibility O
to O
diabetes B
. O

The O
gene O
, O
termed O
low O
- O
density O
lipoprotein O
receptor O
related O
protein O
5 O
( O
LRP5 O
) O
, O
encodes O
a O
protein O
of O
1615 O
amino O
acids O
that O
contains O
conserved O
modules O
which O
are O
characteristic O
of O
the O
low O
- O
density O
lipoprotein O
( O
LDL O
) O
receptor O
family O
. O

These O
modules O
include O
a O
putative O
signal O
peptide O
for O
protein O
export O
, O
four O
epidermal O
growth O
factor O
( O
EGF O
) O
repeats O
with O
associated O
spacer O
domains O
, O
three O
LDL O
- O
receptor O
( O
LDLR O
) O
repeats O
, O
a O
single O
transmembrane O
spanning O
domain O
, O
and O
a O
cytoplasmic O
domain O
. O

The O
encoded O
protein O
has O
a O
unique O
organization O
of O
EGF O
and O
LDLR O
repeats O
; O
therefore O
, O
LRP5 O
likely O
represents O
a O
new O
category O
of O
the O
LDLR O
family O
. O

Both O
human O
and O
mouse O
LRP5 O
cDNAs O
have O
been O
isolated O
and O
the O
encoded O
mature O
proteins O
are O
95 O
% O
identical O
, O
indicating O
a O
high O
degree O
of O
evolutionary O
conservation O
. O
. O

The O
APC B
variants O
I1307K O
and O
E1317Q O
are O
associated O
with O
colorectal B
tumors I
, O
but O
not O
always O
with O
a O
family O
history O
. O

Classical O
familial I
adenomatous I
polyposis I
( O
FAP B
) O
is O
a O
high O
- O
penetrance O
autosomal B
dominant I
disease I
that O
predisposes O
to O
hundreds O
or O
thousands O
of O
colorectal B
adenomas I
and O
carcinoma B
and O
that O
results O
from O
truncating O
mutations O
in O
the O
APC B
gene O
. O

A O
variant O
of O
FAP O
is O
attenuated O
adenomatous I
polyposis I
coli I
, O
which O
results O
from O
germ O
- O
line O
mutations O
in O
the O
5 O
and O
3 O
regions O
of O
the O
APC B
gene O
. O

Attenuated B
adenomatous I
polyposis I
coli I
patients O
have O
" O
multiple O
" O
colorectal B
adenomas I
( O
typically O
fewer O
than O
100 O
) O
without O
the O
florid O
phenotype O
of O
classical O
FAP B
. O

Another O
group O
of O
patients O
with O
multiple B
adenomas I
has O
no O
mutations O
in O
the O
APC B
gene O
, O
and O
their O
phenotype O
probably O
results O
from O
variation O
at O
a O
locus O
, O
or O
loci O
, O
elsewhere O
in O
the O
genome O
. O

Recently O
, O
however O
, O
a O
missense O
variant O
of O
APC O
( O
I1307K O
) O
was O
described O
that O
confers O
an O
increased O
risk O
of O
colorectal B
tumors I
, O
including O
multiple O
adenomas B
, O
in O
Ashkenazim O
. O

We O
have O
studied O
a O
set O
of O
164 O
patients O
with O
multiple O
colorectal B
adenomas I
and O
/ O
or O
carcinoma B
and O
analyzed O
codons O
1263 O
- O
1377 O
( O
exon O
15G O
) O
of O
the O
APC B
gene O
for O
germ O
- O
line O
variants O
. O

Three O
patients O
with O
the O
I1307K O
allele O
were O
detected O
, O
each O
of O
Ashkenazi O
descent O
. O

Four O
patients O
had O
a O
germ O
- O
line O
E1317Q O
missense O
variant O
of O
APC O
that O
was O
not O
present O
in O
controls O
; O
one O
of O
these O
individuals O
had O
an O
unusually O
large O
number O
of O
metaplastic B
polyps I
of I
the I
colorectum I
. O

There O
is O
increasing O
evidence O
that O
there O
exist O
germ O
- O
line O
variants O
of O
the O
APC B
gene O
that O
predispose O
to O
the O
development O
of O
multiple O
colorectal B
adenomas I
and O
carcinoma B
, O
but O
without O
the O
florid O
phenotype O
of O
classical O
FAP B
, O
and O
possibly O
with O
importance O
for O
colorectal B
cancer I
risk O
in O
the O
general O
population O
. O
. O

Genomic O
structure O
of O
the O
human O
congenital B
chloride I
diarrhea I
( O
CLD B
) O
gene O
. O

Congenital B
chloride I
diarrhea I
( O
CLD B
) O
is O
caused O
by O
mutations O
in O
a O
gene O
which O
encodes O
an O
intestinal O
anion O
transporter O
. O

We O
report O
here O
the O
complete O
genomic O
organization O
of O
the O
human O
CLD B
gene O
which O
spans O
approximately O
39kb O
, O
and O
comprises O
21 O
exons O
. O

All O
exon O
/ O
intron O
boundaries O
conform O
to O
the O
GT O
/ O
AG O
rule O
. O

An O
analysis O
of O
the O
putative O
promoter O
region O
sequence O
shows O
a O
putative O
TATA O
box O
and O
predicts O
multiple O
transcription O
factor O
binding O
sites O
. O

The O
genomic O
structure O
was O
determined O
using O
DNA O
from O
several O
sources O
including O
multiple O
large O
- O
insert O
libaries O
and O
genomic O
DNA O
from O
Finnish O
CLD B
patients O
and O
controls O
. O

Exon O
- O
specific O
primers O
developed O
in O
this O
study O
will O
facilitate O
mutation O
screening O
studies O
of O
patients O
with O
the O
disease O
. O

Genomic O
sequencing O
of O
a O
BAC O
clone O
H O
_ O
RG364P16 O
revealed O
the O
presence O
of O
another O
, O
highly O
homologous O
gene O
3 O
of O
the O
CLD B
gene O
, O
with O
a O
similar O
genomic O
structure O
, O
recently O
identified O
as O
the O
Pendred B
syndrome I
gene O
( O
PDS B
) O
. O
. O

The O
APCI1307K O
allele O
and O
cancer B
risk O
in O
a O
community O
- O
based O
study O
of O
Ashkenazi O
Jews O
. O

Mutations O
in O
APC O
are O
classically O
associated O
with O
familial B
adenomatous I
polyposis I
( O
FAP B
) O
, O
a O
highly O
penetrant O
autosomal B
dominant I
disorder I
characterized O
by O
multiple O
intestinal B
polyps I
and O
, O
without O
surgical O
intervention O
, O
the O
development O
of O
colorectal B
cancer I
( O
CRC B
) O
. O

APC O
is O
a O
tumour B
- O
suppressor O
gene O
, O
and O
somatic O
loss O
occurs O
in O
tumours B
. O

The O
germline O
T O
- O
to O
- O
A O
transversion O
responsible O
for O
the O
APC O
I1307K O
allele O
converts O
the O
wild O
- O
type O
sequence O
to O
a O
homopolymer O
tract O
( O
A8 O
) O
that O
is O
genetically O
unstable O
and O
prone O
to O
somatic O
mutation O
. O

The O
I1307K O
allele O
was O
found O
in O
6 O
. O

1 O
% O
of O
unselected O
Ashkenazi O
Jews O
and O
higher O
proportions O
of O
Ashkenazim O
with O
family O
or O
personal O
histories O
of O
CRC B
( O
ref O
. O
2 O
) O
. O

To O
evaluate O
the O
role O
of O
I1307K O
in O
cancer B
, O
we O
genotyped O
5 O
, O
081 O
Ashkenazi O
volunteers O
in O
a O
community O
survey O
. O

Risk O
of O
developing O
colorectal B
, I
breast I
and I
other I
cancers I
were O
compared O
between O
genotyped O
I1307K O
carriers O
and O
non O
- O
carriers O
and O
their O
first O
- O
degree O
relatives O
. O

Sperm O
DNA O
analysis O
in O
a O
Friedreich B
ataxia I
premutation O
carrier O
suggests O
both O
meiotic O
and O
mitotic O
expansion O
in O
the O
FRDA B
gene O
. O

Friedreich B
ataxia I
is O
usually O
caused O
by O
an O
expansion O
of O
a O
GAA O
trinucleotide O
repeat O
in O
intron O
1 O
of O
the O
FRDA B
gene O
. O

Occasionally O
, O
a O
fully O
expanded O
allele O
has O
been O
found O
to O
arise O
from O
a O
premutation O
of O
100 O
or O
less O
triplet O
repeats O
. O

We O
have O
examined O
the O
sperm O
DNA O
of O
a O
premutation O
carrier O
. O

This O
mans O
leucocyte O
DNA O
showed O
one O
normal O
allele O
and O
one O
allele O
of O
approximately O
100 O
repeats O
. O

His O
sperm O
showed O
an O
expanded O
allele O
in O
a O
tight O
range O
centering O
on O
a O
size O
of O
approximately O
320 O
trinucleotide O
repeats O
. O

His O
affected O
son O
has O
repeat O
sizes O
of O
1040 O
and O
540 O
. O

These O
data O
suggest O
that O
expansion O
occurs O
in O
two O
stages O
, O
the O
first O
during O
meiosis O
followed O
by O
a O
second O
mitotic O
expansion O
. O

We O
also O
show O
that O
in O
all O
informative O
carrier O
father O
to O
affected O
child O
transmissions O
, O
with O
the O
notable O
exception O
of O
the O
premutation O
carrier O
, O
the O
expansion O
size O
decreases O
. O
. O

The O
R496H O
mutation O
of O
arylsulfatase O
A O
does O
not O
cause O
metachromatic B
leukodystrophy I
. O

Deficiency B
of I
arylsulfatase I
A I
( O
ARSA O
) O
enzyme O
activity O
causes O
metachromatic B
leukodystrophy I
( O
MLD B
) O
. O

A O
number O
of O
ARSA O
gene O
mutations O
responsible O
for O
MLD B
have O
been O
identified O
. O

Recently O
, O
the O
R496H O
mutation O
of O
ARSA O
was O
proposed O
to O
be O
a O
cause O
of O
MLD B
( O
Draghia O
et O
al O
. O
, O
1997 O
) O
. O

We O
have O
investigated O
the O
R496H O
mutation O
and O
found O
this O
mutation O
at O
a O
relatively O
high O
frequency O
in O
an O
African O
American O
population O
( O
f O
= O
0 O
. O
09 O
, O
n O
= O
61 O
subjects O
) O
. O

The O
ARSA O
enzyme O
activity O
in O
subjects O
with O
and O
without O
the O
R496H O
mutation O
was O
determined O
and O
found O
to O
be O
normal O
. O

It O
is O
therefore O
concluded O
that O
the O
R496H O
mutation O
of O
ARSA O
does O
not O
negatively O
influence O
the O
activity O
of O
ARSA O
and O
is O
not O
a O
cause O
of O
MLD B

Down O
- O
regulation O
of O
transmembrane O
carbonic O
anhydrases O
in O
renal B
cell I
carcinoma I
cell O
lines O
by O
wild O
- O
type O
von B
Hippel I
- I
Lindau I
transgenes O
. O

To O
discover O
genes O
involved O
in O
von B
Hippel I
- I
Lindau I
( O
VHL O
) O
- O
mediated O
carcinogenesis O
, O
we O
used O
renal B
cell I
carcinoma I
cell O
lines O
stably O
transfected O
with O
wild O
- O
type O
VHL O
- O
expressing O
transgenes O
. O

Large O
- O
scale O
RNA O
differential O
display O
technology O
applied O
to O
these O
cell O
lines O
identified O
several O
differentially O
expressed O
genes O
, O
including O
an O
alpha O
carbonic O
anhydrase O
gene O
, O
termed O
CA12 O
. O

The O
deduced O
protein O
sequence O
was O
classified O
as O
a O
one O
- O
pass O
transmembrane O
CA O
possessing O
an O
apparently O
intact O
catalytic O
domain O
in O
the O
extracellular O
CA O
module O
. O

Reintroduced O
wild O
- O
type O
VHL O
strongly O
inhibited O
the O
overexpression O
of O
the O
CA12 O
gene O
in O
the O
parental O
renal B
cell I
carcinoma I
cell O
lines O
. O

Similar O
results O
were O
obtained O
with O
CA9 O
, O
encoding O
another O
transmembrane O
CA O
with O
an O
intact O
catalytic O
domain O
. O

Although O
both O
domains O
of O
the O
VHL B
protein O
contribute O
to O
regulation O
of O
CA12 O
expression O
, O
the O
elongin O
binding O
domain O
alone O
could O
effectively O
regulate O
CA9 O
expression O
. O

We O
mapped O
CA12 O
and O
CA9 O
loci O
to O
chromosome O
bands O
15q22 O
and O
17q21 O
. O

2 O
respectively O
, O
regions O
prone O
to O
amplification O
in O
some O
human O
cancers B
. O

Additional O
experiments O
are O
needed O
to O
define O
the O
role O
of O
CA O
IX O
and O
CA O
XII O
enzymes O
in O
the O
regulation O
of O
pH O
in O
the O
extracellular O
microenvironment O
and O
its O
potential O
impact O
on O
cancer B
cell O
growth O
. O

A O
gene O
encoding O
a O
transmembrane O
protein O
is O
mutated O
in O
patients O
with O
diabetes B
mellitus I
and O
optic B
atrophy I
( O
Wolfram B
syndrome I
) O
. O

Wolfram B
syndrome I
( O
WFS B
; O
OMIM O
222300 O
) O
is O
an O
autosomal B
recessive I
neurodegenerative I
disorder I
defined O
by O
young O
- O
onset O
non B
- I
immune I
insulin I
- I
dependent I
diabetes I
mellitus I
and O
progressive O
optic B
atrophy I
. O

Linkage O
to O
markers O
on O
chromosome O
4p O
was O
confirmed O
in O
five O
families O
. O

On O
the O
basis O
of O
meiotic O
recombinants O
and O
disease O
- O
associated O
haplotypes O
, O
the O
WFS B
gene O
was O
localized O
to O
a O
BAC O
/ O
P1 O
contig O
of O
less O
than O
250 O
kb O
. O

Mutations O
in O
a O
novel O
gene O
( O
WFS1 O
) O
encoding O
a O
putative O
transmembrane O
protein O
were O
found O
in O
all O
affected O
individuals O
in O
six O
WFS B
families O
, O
and O
these O
mutations O
were O
associated O
with O
the O
disease O
phenotype O
. O

WFS1 O
appears O
to O
function O
in O
survival O
of O
islet O
beta O
- O
cells O
and O
neurons O
. O
. O

Stable O
interaction O
between O
the O
products O
of O
the O
BRCA1 O
and O
BRCA2 O
tumor B
suppressor O
genes O
in O
mitotic O
and O
meiotic O
cells O
. O

BRCA1 O
and O
BRCA2 O
account O
for O
most O
cases O
of O
familial O
, O
early O
onset O
breast B
and I
/ I
or I
ovarian I
cancer I
and O
encode O
products O
that O
each O
interact O
with O
hRAD51 O
. O

Results O
presented O
here O
show O
that O
BRCA1 O
and O
BRCA2 O
coexist O
in O
a O
biochemical O
complex O
and O
colocalize O
in O
subnuclear O
foci O
in O
somatic O
cells O
and O
on O
the O
axial O
elements O
of O
developing O
synaptonemal O
complexes O
. O

Like O
BRCA1 O
and O
RAD51 O
, O
BRCA2 O
relocates O
to O
PCNA O
+ O
replication O
sites O
following O
exposure O
of O
S O
phase O
cells O
to O
hydroxyurea O
or O
UV O
irradiation O
. O

Thus O
, O
BRCA1 O
and O
BRCA2 O
participate O
, O
together O
, O
in O
a O
pathway O
( O
s O
) O
associated O
with O
the O
activation O
of O
double O
- O
strand O
break O
repair O
and O
/ O
or O
homologous O
recombination O
. O

Dysfunction O
of O
this O
pathway O
may O
be O
a O
general O
phenomenon O
in O
the O
majority O
of O
cases O
of O
hereditary B
breast I
and I
/ I
or I
ovarian I
cancer I
. O
. O

A O
novel O
Arg362Ser O
mutation O
in O
the O
sterol O
27 O
- O
hydroxylase O
gene O
( O
CYP27 O
) O
: O
its O
effects O
on O
pre O
- O
mRNA O
splicing O
and O
enzyme O
activity O
. O

A O
novel O
C O
to O
A O
mutation O
in O
the O
sterol O
27 O
- O
hydroxylase O
gene O
( O
CYP27 O
) O
was O
identified O
by O
sequencing O
amplified O
CYP27 O
gene O
products O
from O
a O
patient O
with O
cerebrotendinous B
xanthomatosis I
( O
CTX B
) O
. O

The O
mutation O
changed O
the O
adrenodoxin O
cofactor O
binding O
residue O
362Arg O
to O
362Ser O
( O
CGT O
362Arg O
to O
AGT O
362Ser O
) O
, O
and O
was O
responsible O
for O
deficiency B
in I
the I
sterol I
27 I
- I
hydroxylase I
activity I
, O
as O
confirmed O
by O
expression O
of O
mutant O
cDNA O
into O
COS O
- O
1 O
cells O
. O

Quantitative O
analysis O
showed O
that O
the O
expression O
of O
CYP27 O
gene O
mRNA O
in O
the O
patient O
represented O
52 O
. O

5 O
% O
of O
the O
normal O
level O
. O

As O
the O
mutation O
occurred O
at O
the O
penultimate O
nucleotide O
of O
exon O
6 O
( O
- O
2 O
position O
of O
exon O
6 O
- O
intron O
6 O
splice O
site O
) O
of O
the O
gene O
, O
we O
hypothesized O
that O
the O
mutation O
may O
partially O
affect O
the O
normal O
splicing O
efficiency O
in O
exon O
6 O
and O
cause O
alternative O
splicing O
elsewhere O
, O
which O
resulted O
in O
decreased O
transcript O
in O
the O
patient O
. O

Transfection O
of O
constructed O
minigenes O
, O
with O
or O
without O
the O
mutation O
, O
into O
COS O
- O
1 O
cells O
confirmed O
that O
the O
mutant O
minigene O
was O
responsible O
for O
a O
mRNA O
species O
alternatively O
spliced O
at O
an O
activated O
cryptic O
5 O
splice O
site O
88 O
bp O
upstream O
from O
the O
3 O
end O
of O
exon O
6 O
. O

Our O
data O
suggest O
that O
the O
C O
to O
A O
mutation O
at O
the O
penultimate O
nucleotide O
of O
exon O
6 O
of O
the O
CYP27 O
gene O
not O
only O
causes O
the O
deficiency B
in I
the I
sterol I
27 I
- I
hydroxylase I
activity I
, O
but O
also O
partially O
leads O
to O
alternative O
pre O
- O
mRNA O
splicing O
of O
the O
gene O
. O

To O
our O
knowledge O
, O
this O
is O
the O
first O
report O
regarding O
effects O
on O
pre O
- O
mRNA O
splicing O
of O
a O
mutation O
at O
the O
- O
2 O
position O
of O
a O
5 O
splice O
site O
. O

ATM O
germline O
mutations O
in O
classical O
ataxia I
- I
telangiectasia I
patients O
in O
the O
Dutch O
population O
. O

Germline O
mutations O
in O
the O
ATM O
gene O
are O
responsible O
for O
the O
autosomal B
recessive I
disorder I
ataxia B
- I
telangiectasia I
( O
A B
- I
T I
) O
. O

In O
our O
study O
, O
we O
have O
determined O
the O
ATM O
mutation O
spectrum O
in O
19 O
classical O
A B
- I
T I
patients O
, O
including O
some O
immigrant O
populations O
, O
as O
well O
as O
12 O
of O
Dutch O
ethnic O
origin O
. O

Both O
the O
protein O
truncation O
test O
( O
PTT O
) O
and O
the O
restriction O
endonuclease O
fingerprinting O
( O
REF O
) O
method O
were O
used O
and O
compared O
for O
their O
detection O
efficiency O
, O
identifying O
76 O
% O
and O
60 O
% O
of O
the O
mutations O
, O
respectively O
. O

Most O
patients O
were O
found O
to O
be O
compound O
heterozygote O
. O

Seventeen O
mutations O
were O
distinct O
, O
of O
which O
10 O
were O
not O
reported O
previously O
. O

Mutations O
are O
small O
deletions O
or O
point O
mutations O
frequently O
affecting O
splice O
sites O
. O

Moreover O
, O
a O
16 O
. O

7 O
- O
kb O
genomic O
deletion O
of O
the O
3 O
end O
of O
the O
gene O
, O
most O
likely O
a O
result O
of O
recombination O
between O
two O
LINE O
elements O
, O
was O
identified O
. O

The O
most O
frequently O
found O
mutation O
, O
identified O
in O
three O
unrelated O
Turkish O
A B
- I
T I
individuals O
, O
was O
previously O
described O
to O
be O
a O
Turkish O
A B
- I
T I
founder O
mutation O
. O

The O
presence O
of O
a O
founder O
mutation O
among O
relatively O
small O
ethnic O
population O
groups O
in O
Western O
Europe O
could O
indicate O
a O
high O
carrier O
frequency O
in O
such O
communities O
. O

In O
patients O
of O
Dutch O
ethnic O
origin O
, O
however O
, O
no O
significant O
founder O
effect O
could O
be O
identified O
. O

The O
observed O
genetic O
heterogeneity O
including O
the O
relative O
high O
percentage O
of O
splice O
- O
site O
mutations O
had O
no O
reflection O
on O
the O
phenotype O
. O

All O
patients O
manifested O
classical O
A B
- I
T I
and O
increased O
cellular O
radioresistant O
DNA O
synthesis O
. O

Determination O
of O
the O
genomic O
structure O
of O
the O
COL4A4 O
gene O
and O
of O
novel O
mutations O
causing O
autosomal B
recessive I
Alport I
syndrome I
. O

Autosomal B
recessive I
Alport I
syndrome I
is O
a O
progressive O
hematuric B
glomerulonephritis I
characterized O
by O
glomerular B
basement I
membrane I
abnormalities I
and O
associated O
with O
mutations O
in O
either O
the O
COL4A3 O
or O
the O
COL4A4 O
gene O
, O
which O
encode O
the O
alpha3 O
and O
alpha4 O
type O
IV O
collagen O
chains O
, O
respectively O
. O

To O
date O
, O
mutation O
screening O
in O
the O
two O
genes O
has O
been O
hampered O
by O
the O
lack O
of O
genomic O
structure O
information O
. O

We O
report O
here O
the O
complete O
characterization O
of O
the O
48 O
exons O
of O
the O
COL4A4 O
gene O
, O
a O
comprehensive O
gene O
screen O
, O
and O
the O
subsequent O
detection O
of O
10 O
novel O
mutations O
in O
eight O
patients O
diagnosed O
with O
autosomal B
recessive I
Alport I
syndrome I
. O

Furthermore O
, O
we O
identified O
a O
glycine O
to O
alanine O
substitution O
in O
the O
collagenous O
domain O
that O
is O
apparently O
silent O
in O
the O
heterozygous O
carriers O
, O
in O
11 O
. O

5 O
% O
of O
all O
control O
individuals O
, O
and O
in O
one O
control O
individual O
homozygous O
for O
this O
glycine O
substitution O
. O

There O
has O
been O
no O
previous O
finding O
of O
a O
glycine O
substitution O
that O
is O
not O
associated O
with O
any O
obvious O
phenotype O
in O
homozygous O
individuals O
. O

Founder O
BRCA1 O
and O
BRCA2 O
mutations O
in O
French O
Canadian O
breast B
and I
ovarian I
cancer I
families O
. O

We O
have O
identified O
four O
mutations O
in O
each O
of O
the O
breast B
cancer I
- O
susceptibility O
genes O
, O
BRCA1 O
and O
BRCA2 O
, O
in O
French O
Canadian O
breast B
cancer I
and O
breast B
/ I
ovarian I
cancer I
families O
from O
Quebec O
. O

To O
identify O
founder O
effects O
, O
we O
examined O
independently O
ascertained O
French O
Canadian O
cancer B
families O
for O
the O
distribution O
of O
these O
eight O
mutations O
. O

Mutations O
were O
found O
in O
41 O
of O
97 O
families O
. O

Six O
of O
eight O
mutations O
were O
observed O
at O
least O
twice O
. O

The O
BRCA1 O
C4446T O
mutation O
was O
the O
most O
common O
mutation O
found O
, O
followed O
by O
the O
BRCA2 O
8765delAG O
mutation O
. O

Together O
, O
these O
mutations O
were O
found O
in O
28 O
of O
41 O
families O
identified O
to O
have O
a O
mutation O
. O

The O
odds O
of O
detection O
of O
any O
of O
the O
four O
BRCA1 O
mutations O
was O
18 O
. O

7x O
greater O
if O
one O
or O
more O
cases O
of O
ovarian B
cancer I
were O
also O
present O
in O
the O
family O
. O

The O
odds O
of O
detection O
of O
any O
of O
the O
four O
BRCA2 O
mutations O
was O
5 O
. O

3x O
greater O
if O
there O
were O
at O
least O
five O
cases O
of O
breast B
cancer I
in O
the O
family O
. O

Interestingly O
, O
the O
presence O
of O
a O
breast B
cancer I
case O
< O
36 O
years O
of O
age O
was O
strongly O
predictive O
of O
the O
presence O
of O
any O
of O
the O
eight O
mutations O
screened O
. O

Carriers O
of O
the O
same O
mutation O
, O
from O
different O
families O
, O
shared O
similar O
haplotypes O
, O
indicating O
that O
the O
mutant O
alleles O
were O
likely O
to O
be O
identical O
by O
descent O
for O
a O
mutation O
in O
the O
founder O
population O
. O

The O
identification O
of O
common O
BRCA1 O
and O
BRCA2 O
mutations O
will O
facilitate O
carrier O
detection O
in O
French O
Canadian O
breast B
cancer I
and O
breast B
/ I
ovarian I
cancer I
families O
. O

Are O
Dp71 O
and O
Dp140 O
brain O
dystrophin O
isoforms O
related O
to O
cognitive B
impairment I
in O
Duchenne B
muscular I
dystrophy I
? O

Molecular O
study O
and O
neuropsychological O
analysis O
were O
performed O
concurrently O
on O
49 O
patients O
with O
Duchenne B
muscular I
dystrophy I
( O
DMD B
) O
in O
order O
to O
find O
a O
molecular O
explanation O
for O
the O
cognitive B
impairment I
observed O
in O
most O
DMD B
patients O
. O

Complete O
analysis O
of O
the O
dystrophin O
gene O
was O
performed O
to O
define O
the O
localization O
of O
deletions O
and O
duplications O
in O
relation O
to O
the O
different O
DMD B
promoters O
. O

Qualitative O
analysis O
of O
the O
Dp71 O
transcript O
and O
testing O
for O
the O
specific O
first O
exon O
of O
Dp140 O
were O
also O
carried O
out O
. O

Neuropsychological O
analysis O
assessed O
verbal O
and O
visuospatial O
intelligence O
, O
verbal O
memory O
, O
and O
reading O
skills O
. O

Comparison O
of O
molecular O
and O
psychometric O
findings O
demonstrated O
that O
deletions O
and O
duplications O
that O
were O
localized O
in O
the O
distal O
part O
of O
the O
gene O
seemed O
to O
be O
preferentially O
associated O
with O
cognitive B
impairment I
. O

Two O
altered O
Dp71 O
transcripts O
and O
two O
deleted O
Dp140 O
DNA O
sequences O
were O
found O
in O
four O
patients O
with O
severe O
cerebral B
dysfunction I
. O

These O
findings O
suggest O
that O
some O
sequences O
located O
in O
the O
distal O
part O
of O
the O
gene O
and O
, O
in O
particular O
, O
some O
DMD B
isoforms O
expressed O
in O
the O
brain O
may O
be O
related O
to O
the O
cognitive B
impairment I
associated O
with O
DMD B
. O
. O

I1307K O
APC O
and O
hMLH1 O
mutations O
in O
a O
non O
- O
Jewish O
family O
with O
hereditary B
non I
- I
polyposis I
colorectal I
cancer I
. O

We O
describe O
a O
French O
Canadian O
hereditary B
non I
- I
polyposis I
colorectal I
cancer I
( O
HNPCC B
) O
kindred O
which O
carries O
a O
novel O
truncating O
mutation O
in O
hMLH1 O
. O

Interestingly O
, O
the O
I1307K O
APC B
polymorphism O
, O
associated O
with O
an O
increased O
risk O
of O
colorectal B
cancer I
, O
is O
also O
present O
in O
this O
family O
. O

The O
I1307K O
polymorphism O
has O
previously O
only O
been O
identified O
in O
individuals O
of O
self O
- O
reported O
Ashkenazi O
Jewish O
origins O
. O

In O
addition O
, O
in O
this O
family O
, O
there O
appears O
to O
be O
no O
relationship O
between O
the O
I1307K O
polymorphism O
and O
the O
presence O
or O
absence O
of O
cancer B
. O
. O

Identification O
of O
a O
novel O
mutation O
of O
the O
CPO O
gene O
in O
a O
Japanese O
hereditary B
coproporphyria I
family O
. O

Hereditary B
coproporphyria I
( O
HCP B
) O
is O
an O
autosomal B
dominant I
disease I
characterized O
by O
a O
deficiency B
of I
coproporphyrinogen I
oxidase I
( O
CPO O
) O
caused O
by O
a O
mutation O
in O
the O
CPO O
gene O
. O

Only O
11 O
mutations O
of O
the O
gene O
have O
been O
reported O
in O
HCP B
patients O
. O

We O
report O
another O
mutation O
in O
a O
Japanese O
family O
. O

Polymerase O
chain O
reaction O
- O
single O
strand O
conformational O
polymorphism O
and O
direct O
sequence O
analyses O
demonstrated O
a O
C O
to O
T O
substitution O
in O
exon O
1 O
of O
the O
CPO O
gene O
at O
nucleotide O
position O
85 O
, O
which O
lies O
in O
the O
putative O
presequence O
for O
targeting O
to O
mitochondria O
. O

This O
mutation O
changes O
the O
codon O
for O
glutamine O
to O
a O
termination O
codon O
at O
amino O
acid O
position O
29 O
. O

MaeI O
restriction O
analysis O
showed O
two O
other O
carriers O
in O
the O
family O
. O

The O
C O
- O
T O
mutation O
is O
located O
within O
a O
recently O
proposed O
putative O
alternative O
translation O
initiation O
codon O
( O
TIC O
- O
1 O
) O
, O
supporting O
that O
TIC O
- O
1 O
is O
the O
real O
TIC O
rather O
than O
TIC O
- O
2 O
. O
. O

Human O
complement I
factor I
H I
deficiency I
associated O
with O
hemolytic B
uremic I
syndrome I
. O

This O
study O
reports O
on O
six O
cases O
of O
deficiency B
in I
the I
human I
complement I
regulatory I
protein I
Factor I
H I
( O
FH B
) O
in O
the O
context O
of O
an O
acute O
renal I
disease I
. O

Five O
of O
the O
cases O
were O
observed O
in O
children O
presenting O
with O
idiopathic O
hemolytic I
uremic I
syndrome I
( O
HUS B
) O
. O

Two O
of O
the O
children O
exhibited O
a O
homozygous O
deficiency O
characterized O
by O
the O
absence O
of O
the O
150 O
- O
kD O
form O
of O
Factor O
H O
and O
the O
presence O
, O
upon O
immunoblotting O
, O
of O
the O
42 O
- O
kD O
Factor O
H O
- O
like O
protein O
1 O
( O
FHL O
- O
1 O
) O
and O
other O
FH O
- O
related O
protein O
( O
FHR O
) O
bands O
. O

Southern O
blot O
and O
PCR O
analysis O
of O
DNA O
of O
one O
patient O
with O
homozygous O
deficiency O
ruled O
out O
the O
presence O
of O
a O
large O
deletion O
of O
the O
FH B
gene O
as O
the O
underlying O
defect O
for O
the O
deficiency O
. O

The O
other O
four O
children O
presented O
with O
heterozygous O
deficiency O
and O
exhibited O
a O
normal O
immunoblotting O
pattern O
of O
proteins O
of O
the O
FH B
family O
. O

Factor B
H I
deficiency I
is O
the O
only O
complement B
deficiency I
associated O
with O
HUS B
. O

These O
observations O
suggest O
a O
role O
for O
FH O
and O
/ O
or O
FH O
receptors O
in O
the O
pathogenesis O
of O
idiopathic O
HUS B
. O
. O

Further O
evidence O
for O
a O
major O
ancient O
mutation O
underlying O
myotonic B
dystrophy I
from O
linkage O
disequilibrium O
studies O
in O
the O
Japanese O
population O
. O

The O
myotonic B
dystrophy I
( O
DM B
) O
mutation O
is O
an O
unstable O
( O
CTG O
) O
n O
repeat O
, O
present O
at O
a O
copy O
number O
of O
5 O
- O
37 O
repeats O
on O
normal O
chromosomes O
but O
amplified O
to O
50 O
- O
3000 O
copies O
on O
DM B
chromosomes O
. O

Previous O
findings O
in O
Caucasian O
populations O
of O
a O
DM B
founder O
chromosome O
raise O
a O
question O
about O
the O
molecular O
events O
involved O
in O
the O
expansion O
mutation O
. O

To O
investigate O
whether O
a O
founder O
chromosome O
for O
the O
DM B
mutation O
exists O
in O
the O
Japanese O
population O
, O
we O
genotyped O
families O
using O
polymorphic O
markers O
near O
the O
( O
CTG O
) O
n O
repeat O
region O
and O
constructed O
haplotypes O
. O

Six O
different O
haplotypes O
were O
found O
and O
DM B
alleles O
were O
always O
haplotype O
A O
. O

To O
find O
an O
origin O
of O
the O
( O
CTG O
) O
n O
repeat O
mutation O
and O
to O
investigate O
the O
mechanism O
of O
the O
expansion O
mutation O
in O
the O
Japanese O
population O
we O
have O
studied O
90 O
Japanese O
DM B
families O
comprising O
190 O
affected O
and O
130 O
unaffected O
members O
. O

The O
results O
suggest O
that O
a O
few O
common O
ancestral O
mutations O
in O
both O
Caucasian O
and O
Japanese O
populations O
have O
originated O
by O
expansion O
of O
an O
ancestral O
n O
= O
5 O
repeat O
to O
n O
= O
19 O
- O
37 O
copies O
. O

These O
data O
support O
multistep O
models O
of O
triplet O
repeat O
expansion O
that O
have O
been O
proposed O
for O
both O
DM B
and O
Friedreichs B
ataxia I
. O
. O

The O
molecular O
basis O
of O
C6 B
deficiency I
in O
the O
western O
Cape O
, O
South O
Africa O
. O

Deficiency B
of I
the I
sixth I
component I
of I
human I
complement I
( O
C6 O
) O
has O
been O
reported O
in O
a O
number O
of O
families O
from O
the O
western O
Cape O
, O
South O
Africa O
. O

Meningococcal B
disease I
is O
endemic O
in O
the O
Cape O
and O
almost O
all O
pedigrees O
of O
total B
C6 I
deficiency I
( O
C6Q0 O
) O
have O
been O
ascertained O
because O
of O
recurrent O
disease O
. O

We O
have O
sequenced O
the O
expressed O
exons O
of O
the O
C6 O
gene O
from O
selected O
cases O
and O
have O
found O
three O
molecular O
defects O
leading O
to O
total O
deficiency I
879delG O
, O
which O
is O
the O
common O
defect O
in O
the O
Cape O
and O
hitherto O
unreported O
, O
and O
1195delC O
and O
1936delG O
, O
which O
have O
been O
previously O
reported O
in O
African O
- O
Americans O
. O

We O
also O
show O
that O
the O
879delG O
and O
1195delC O
defects O
are O
associated O
with O
characteristic O
C6 O
/ O
C7 O
region O
DNA O
marker O
haplotypes O
, O
although O
small O
variations O
were O
observed O
. O

The O
1936delG O
defect O
was O
observed O
only O
once O
in O
the O
Cape O
, O
but O
its O
associated O
haplotype O
could O
be O
deduced O
. O

The O
data O
from O
the O
haplotypes O
indicate O
that O
these O
three O
molecular O
defects O
account O
for O
the O
defects O
in O
all O
the O
38 O
unrelated O
C6Q0 O
individuals O
we O
have O
studied O
from O
the O
Cape O
. O

We O
have O
also O
observed O
the O
879delG O
defect O
in O
two O
Dutch O
C6 B
- I
deficient I
kindreds O
, O
but O
the O
879delG O
defect O
in O
the O
Cape O
probably O
did O
not O
come O
from O
The O
Netherlands O
. O
. O

Complement B
C7 I
deficiency I
: O
seven O
further O
molecular O
defects O
and O
their O
associated O
marker O
haplotypes O
. O

Seven O
further O
molecular O
bases O
of O
C7 B
deficiency I
are O
described O
. O

All O
these O
new O
molecular O
defects O
involve O
single O
- O
nucleotide O
events O
, O
deletions O
and O
substitutions O
, O
some O
of O
which O
alter O
splice O
sites O
, O
and O
others O
codons O
. O

They O
are O
distributed O
along O
the O
C7 O
gene O
, O
but O
predominantly O
towards O
the O
3 O
end O
. O

All O
were O
found O
in O
compound O
heterozygous O
individuals O
. O

The O
C6 O
/ O
C7 O
marker O
haplotypes O
associated O
with O
most O
C7 B
defects I
are O
tabulated O
. O
. O

A O
genome O
- O
wide O
search O
for O
chromosomal O
loci O
linked O
to O
mental O
health O
wellness O
in O
relatives O
at O
high O
risk O
for O
bipolar B
affective I
disorder I
among O
the O
Old O
Order O
Amish O
. O

Bipolar B
affective I
disorder I
( O
BPAD B
; O
manic B
- I
depressive I
illness I
) O
is O
characterized O
by O
episodes O
of O
mania B
and O
/ I
or O
hypomania I
interspersed O
with O
periods O
of O
depression B
. O

Compelling O
evidence O
supports O
a O
significant O
genetic O
component O
in O
the O
susceptibility O
to O
develop O
BPAD B
. O

To O
date O
, O
however O
, O
linkage O
studies O
have O
attempted O
only O
to O
identify O
chromosomal O
loci O
that O
cause O
or O
increase O
the O
risk O
of O
developing O
BPAD B
. O

To O
determine O
whether O
there O
could O
be O
protective O
alleles O
that O
prevent O
or O
reduce O
the O
risk O
of O
developing O
BPAD B
, O
similar O
to O
what O
is O
observed O
in O
other O
genetic B
disorders I
, O
we O
used O
mental B
health I
wellness O
( O
absence O
of O
any O
psychiatric B
disorder I
) O
as O
the O
phenotype O
in O
our O
genome O
- O
wide O
linkage O
scan O
of O
several O
large O
multigeneration O
Old O
Order O
Amish O
pedigrees O
exhibiting O
an O
extremely O
high O
incidence O
of O
BPAD B
. O

We O
have O
found O
strong O
evidence O
for O
a O
locus O
on O
chromosome O
4p O
at O
D4S2949 O
( O
maximum O
GENEHUNTER O
- O
PLUS O
nonparametric O
linkage O
score O
= O
4 O
. O
05 O
, O
P O
= O
5 O
. O
22 O
x O
10 O
( O
- O
4 O
) O
; O
SIBPAL O
Pempirical O
value O
< O
3 O
x O
10 O
( O
- O
5 O
) O
) O
and O
suggestive O
evidence O
for O
a O
locus O
on O
chromosome O
4q O
at O
D4S397 O
( O
maximum O
GENEHUNTER O
- O
PLUS O
nonparametric O
linkage O
score O
= O
3 O
. O
29 O
, O
P O
= O
2 O
. O
57 O
x O
10 O
( O
- O
3 O

) O
; O
SIBPAL O
Pempirical O
value O
< O
1 O
x O
10 O
( O
- O
3 O
) O
) O
that O
are O
linked O
to O
mental B
health I
wellness I
. O

These O
findings O
are O
consistent O
with O
the O
hypothesis O
that O
certain O
alleles O
could O
prevent O
or O
modify O
the O
clinical O
manifestations O
of O
BPAD B
and O
perhaps O
other O
related O
affective B
disorders I
. O

Segregation O
distortion O
in O
myotonic B
dystrophy I
. O

Myotonic B
dystrophy I
( O
DM B
) O
is O
an O
autosomal B
dominant I
disease I
which O
, O
in O
the O
typical O
pedigree O
, O
shows O
a O
three O
generation O
anticipation O
cascade O
. O

This O
results O
in O
infertility B
and O
congenital B
myotonic I
dystrophy I
( O
CDM B
) O
with O
the O
disappearance O
of O
DM B
in O
that O
pedigree O
. O

The O
concept O
of O
segregation O
distortion O
, O
where O
there O
is O
preferential O
transmission O
of O
the O
larger O
allele O
at O
the O
DM B
locus O
, O
has O
been O
put O
forward O
to O
explain O
partially O
the O
maintenance O
of O
DM B
in O
the O
population O
. O

In O
a O
survey O
of O
DM B
in O
Northern O
Ireland O
, O
59 O
pedigrees O
were O
ascertained O
. O

Sibships O
where O
the O
status O
of O
all O
the O
members O
had O
been O
identified O
were O
examined O
to O
determine O
the O
transmission O
of O
the O
DM B
expansion O
from O
affected O
parents O
to O
their O
offspring O
. O

Where O
the O
transmitting O
parent O
was O
male O
, O
58 O
. O

3 O
% O
of O
the O
offspring O
were O
affected O
, O
and O
in O
the O
case O
of O
a O
female O
transmitting O
parent O
, O
68 O
. O

7 O
% O
were O
affected O
. O

Studies O
on O
meiotic O
drive O
in O
DM B
have O
shown O
increased O
transmission O
of O
the O
larger O
allele O
at O
the O
DM B
locus O
in O
non O
- O
DM O
heterozygotes O
for O
CTGn O
. O

This O
study O
provides O
further O
evidence O
that O
the O
DM B
expansion O
tends O
to O
be O
transmitted O
preferentially O
. O

Diagnosis O
of O
hemochromatosis B
. O

If O
untreated O
, O
hemochromatosis B
can O
cause O
serious O
illness O
and O
early O
death O
, O
but O
the O
disease O
is O
still O
substantially O
under O
- O
diagnosed O
. O

The O
cornerstone O
of O
screening O
and O
case O
detection O
is O
the O
measurement O
of O
serum O
transferrin O
saturation O
and O
the O
serum O
ferritin O
level O
. O

Once O
the O
diagnosis O
is O
suspected O
, O
physicians O
must O
use O
serum O
ferritin O
levels O
and O
hepatic O
iron O
stores O
on O
liver O
biopsy O
specimens O
to O
assess O
patients O
for O
the O
presence O
of O
iron O
overload O
. O

Liver O
biopsy O
is O
also O
used O
to O
establish O
the O
presence O
or O
absence O
of O
cirrhosis B
, O
which O
can O
affect O
prognosis O
and O
management O
. O

A O
DNA O
- O
based O
test O
for O
the O
HFE O
gene O
is O
commercially O
available O
, O
but O
its O
place O
in O
the O
diagnosis O
of O
hemochromatosis B
is O
still O
being O
evaluated O
. O

Currently O
, O
the O
most O
useful O
role O
for O
this O
test O
is O
in O
the O
detection O
of O
hemochromatosis B
in O
the O
family O
members O
of O
patients O
with O
a O
proven O
case O
of O
the O
disease O
. O

It O
is O
crucial O
to O
diagnose O
hemochromatosis B
before O
hepatic B
cirrhosis I
develops O
because O
phlebotomy O
therapy O
can O
avert O
serious O
chronic O
disease O
and O
can O
even O
lead O
to O
normal O
life O
expectancy O
. O
. O

Prevalence O
of O
the O
I1307K O
APC B
gene O
variant O
in O
Israeli O
Jews O
of O
differing O
ethnic O
origin O
and O
risk O
for O
colorectal B
cancer I
. O

BACKGROUND O
& O
AIMS O
Israeli O
Jews O
of O
European O
birth O
, O
i O
. O
e O
. O
, O
Ashkenazim O
, O
have O
the O
highest O
colorectal B
cancer I
incidence O
of O
any O
Israeli O
ethnic O
group O
. O

The O
I1307K O
APC B
gene O
variant O
was O
found O
in O
6 O
. O

1 O
% O
of O
American O
Jews O
, O
28 O
% O
of O
their O
familial O
colorectal I
cancer I
cases O
, O
but O
not O
in O
non O
- O
Jews O
. O

We O
assessed O
the O
I1307K O
prevalence O
in O
Israeli O
Jews O
of O
differing O
ethnic O
origin O
and O
risk O
for O
colorectal B
cancer I
. O

METHODS O
DNA O
samples O
from O
500 O
unrelated O
Jews O
of O
European O
or O
non O
- O
European O
origin O
, O
with O
or O
without O
a O
personal O
and O
/ O
or O
family O
history O
of O
neoplasia B
, O
were O
examined O
for O
the O
I1307K O
variant O
by O
the O
allele O
- O
specific O
oligonucleotide O
( O
ASO O
) O
method O
. O

RESULTS O
In O
persons O
at O
average O
risk O
for O
colorectal B
cancer I
, O
I1307K O
was O
found O
in O
5 O
. O

0 O
% O
of O
120 O
European O
and O
1 O
. O

6 O
% O
of O
188 O
non O
- O
European O
Jews O
( O
P O
= O
0 O
. O
08 O
) O
. O

It O
occurred O
in O
15 O
. O

4 O
% O
of O
52 O
Ashkenazi O
Israelis O
with O
familial B
cancer I
( O
P O
= O
0 O
. O
02 O
) O
and O
was O
not O
detected O
in O
51 O
non O
- O
European O
Jews O
at O
increased O
cancer B
risk O
. O

Colorectal B
neoplasia I
occurred O
personally O
or O
in O
the O
families O
of O
13 O
of O
20 O
Ashkenazi O
I1307K O
carriers O
, O
8 O
of O
whom O
also O
had O
a O
personal O
or O
family O
history O
of O
noncolonic B
neoplasia I
. O

CONCLUSIONS O
The O
I1307K O
APC B
variant O
may O
represent O
a O
susceptibility O
gene O
for O
colorectal B
, I
or I
other I
, I
cancers I
in O
Ashkenazi O
Jews O
, O
and O
partially O
explains O
the O
higher O
incidence O
of O
colorectal B
cancer I
in O
European O
Israelis O
. O

Systematic O
analysis O
of O
coproporphyrinogen O
oxidase O
gene O
defects O
in O
hereditary B
coproporphyria I
and O
mutation O
update O
. O

Hereditary B
coproporphyria I
( O
HC B
) O
is O
an O
acute B
hepatic I
porphyria I
with O
autosomal O
dominant O
inheritance O
caused O
by O
deficient O
activity I
of I
coproporphyrinogen I
III I
oxidase I
( O
CPO O
) O
. O

Clinical O
manifestations O
of O
the O
disease O
are O
characterized O
by O
acute O
attacks O
of O
neurological B
dysfunction I
often O
precipitated O
by O
drugs O
, O
fasting O
, O
cyclical O
hormonal O
changes O
, O
or O
infectious B
diseases I
. O

Skin B
photosensitivity I
may O
also O
be O
present O
. O

The O
seven O
exons O
, O
the O
exon O
/ O
intron O
boundaries O
and O
part O
of O
3 O
noncoding O
sequence O
of O
the O
CPO O
gene O
were O
systematically O
analyzed O
by O
an O
exon O
- O
by O
- O
exon O
denaturing O
gradient O
gel O
electrophoresis O
( O
DGGE O
) O
strategy O
followed O
by O
direct O
sequencing O
in O
seven O
unrelated O
heterozygous O
HC B
patients O
from O
France O
, O
Holland O
, O
and O
Czech O
Republic O
. O

Seven O
novel O
mutations O
and O
two O
new O
polymorphisms O
were O
detected O
. O

Among O
these O
mutations O
two O
are O
missense O
( O
G197W O
, O
W427R O
) O
, O
two O
are O
nonsense O
( O
Q306X O
, O
Q385X O
) O
, O
two O
are O
small O
deletions O
( O
662de14bp O
; O
1168del3bp O
removing O
a O
glycine O
at O
position O
390 O
) O
, O
and O
one O
is O
a O
splicing O
mutation O
( O
IVS1 O
- O
15c O
- O
- O
> O
g O
) O
which O
creates O
a O
new O
acceptor O
splice O
site O
. O

The O
pathological O
significance O
of O
the O
point O
mutations O
G197W O
, O
W427R O
, O
and O
the O
in O
- O
frame O
deletion O
390delGly O
were O
assessed O
by O
their O
respective O
expression O
in O
a O
prokaryotic O
system O
using O
site O
- O
directed O
mutagenesis O
. O

These O
mutations O
resulted O
in O
the O
absence O
or O
a O
dramatic O
decrease O
of O
CPO O
activity O
. O

The O
two O
polymorphisms O
were O
localized O
in O
noncoding O
part O
of O
the O
gene O
1 O
) O
a O
C O
/ O
G O
polymorphism O
in O
the O
promotor O
region O
, O
142 O
bp O
upstream O
from O
the O
transcriptional O
initiation O
site O
( O
- O
142C O
/ O
G O
) O
, O
and O
2 O
) O
a O
6 O
bp O
deletion O
polymorphism O
in O
the O
3 O
noncoding O
part O
of O
the O
CPO O
gene O
, O
574 O
bp O
downstream O
of O
the O
last O
base O
of O
the O
normal O
termination O
codon O
( O
+ O
574 O
delATTCTT O
) O
. O

Five O
intragenic O
dimorphisms O
are O
now O
well O
characterized O
and O
the O
high O
degree O
of O
allelic O
heterogeneity O
in O
HC B
is O
demonstrated O
with O
seven O
new O
different O
mutations O
making O
a O
total O
of O
nineteen O
CPO B
gene I
defects I
reported O
so O
far O
. O
. O

Coincidence O
of O
two O
novel O
arylsulfatase O
A O
alleles O
and O
mutation O
459 O
+ O
1G O
> O
A O
within O
a O
family O
with O
metachromatic B
leukodystrophy I
: O
molecular O
basis O
of O
phenotypic O
heterogeneity O
. O

In O
a O
family O
with O
three O
siblings O
, O
one O
developed O
classical O
late O
infantile O
metachromatic B
leukodystrophy I
( O
MLD B
) O
, O
fatal O
at O
age O
5 O
years O
, O
with O
deficient O
arylsulfatase O
A O
( O
ARSA O
) O
activity O
and O
increased O
galactosylsulfatide O
( O
GS O
) O
excretion O
. O

The O
two O
other O
siblings O
, O
apparently O
healthy O
at O
12 O
( O
1 O
/ O
2 O
) O
and O
15 O
years O
, O
respectively O
, O
and O
their O
father O
, O
apparently O
healthy O
as O
well O
, O
presented O
ARSA O
and O
GS O
values O
within O
the O
range O
of O
MLD B
patients O
. O

Mutation O
screening O
and O
sequence O
analysis O
disclosed O
the O
involvement O
of O
three O
different O
ARSA O
mutations O
being O
the O
molecular O
basis O
of O
intrafamilial O
phenotypic O
heterogeneity O
. O

The O
late O
infantile O
patient O
inherited O
from O
his O
mother O
the O
frequent O
0 O
- O
type O
mutation O
459 O
+ O
1G O
> O
A O
, O
and O
from O
his O
father O
a O
novel O
, O
single O
basepair O
microdeletion O
of O
guanine O
at O
nucleotide O
7 O
in O
exon O
1 O
( O
7delG O
) O
. O

The O
two O
clinically O
unaffected O
siblings O
carried O
the O
maternal O
mutation O
459 O
+ O
1G O
> O
A O
and O
, O
on O
their O
paternal O
allele O
, O
a O
novel O
cytosine O
to O
thymidine O
transition O
at O
nucleotide O
2435 O
in O
exon O
8 O
, O
resulting O
in O
substitution O
of O
alanine O
464 O
by O
valine O
( O
A464V O
) O
. O

The O
fathers O
genotype O
thus O
was O
7delG O
/ O
A464V O
. O

Mutation O
A464V O
was O
not O
found O
in O
18 O
unrelated O
MLD B
patients O
and O
50 O
controls O
. O

A464V O
, O
although O
clearly O
modifying O
ARSA O
and O
GS O
levels O
, O
apparently O
bears O
little O
significance O
for O
clinical O
manifestation O
of O
MLD B
, O
mimicking O
the O
frequent O
ARSA O
pseudodeficiency O
allele O
. O

Our O
results O
demonstrate O
that O
in O
certain O
genetic O
conditions O
MLD O
- O
like O
ARSA O
and O
GS O
values O
need O
not O
be O
paralleled O
by O
clinical O
disease O
, O
a O
finding O
with O
serious O
diagnostic O
and O
prognostic O
implications O
. O

Moreover O
, O
further O
ARSA O
alleles O
functionally O
similar O
to O
A464V O
might O
exist O
which O
, O
together O
with O
0 O
- O
type O
mutations O
, O
may O
cause O
pathological O
ARSA O
and O
GS O
levels O
, O
but O
not O
clinical O
outbreak O
of O
the O
disease O
. O
. O

Human O
MLH1 B
deficiency I
predisposes O
to O
hematological B
malignancy I
and O
neurofibromatosis B
type I
1 I
. O

Heterozygous O
germ O
- O
line O
mutations O
in O
the O
DNA O
mismatch O
repair O
genes O
lead O
to O
hereditary B
nonpolyposis I
colorectal I
cancer I
. O

The O
disease O
susceptibility O
of O
individuals O
who O
constitutionally O
lack O
both O
wild O
- O
type O
alleles O
is O
unknown O
. O

We O
have O
identified O
three O
offspring O
in O
a O
hereditary B
nonpolyposis I
colorectal I
cancer I
family O
who O
developed O
hematological B
malignancy I
at O
a O
very O
early O
age O
, O
and O
at O
least O
two O
of O
them O
displayed O
signs O
of O
neurofibromatosis B
type I
1 I
( O
NF1 O
) O
. O

DNA O
sequence O
analysis O
and O
allele O
- O
specific O
amplification O
in O
two O
siblings O
revealed O
a O
homozygous O
MLH1 O
mutation O
( O
C676T O
- O
- O
> O
Arg226Stop O
) O
. O

Thus O
, O
a O
homozygous O
germ O
- O
line O
MLH1 O
mutation O
and O
consequent O
mismatch B
repair I
deficiency I
results O
in O
a O
mutator O
phenotype O
characterized O
by O
leukemia B
and O
/ O
or O
lymphoma B
associated O
with O
neurofibromatosis B
type I
1 I
. O
. O

Missense O
mutations O
in O
the O
most O
ancient O
residues O
of O
the O
PAX6 O
paired O
domain O
underlie O
a O
spectrum O
of O
human O
congenital B
eye I
malformations I
. O

Mutations O
of O
the O
human O
PAX6 O
gene O
underlie O
aniridia B
( O
congenital B
absence I
of I
the I
iris I
) O
, O
a O
rare O
dominant O
malformation I
of I
the I
eye I
. O

The O
spectrum O
of O
PAX6 O
mutations O
in O
aniridia B
patients O
is O
highly O
biased O
, O
with O
92 O
% O
of O
all O
reported O
mutations O
leading O
to O
premature O
truncation O
of O
the O
protein O
( O
nonsense O
, O
splicing O
, O
insertions O
and O
deletions O
) O
and O
just O
2 O
% O
leading O
to O
substitution O
of O
one O
amino O
acid O
by O
another O
( O
missense O
) O
. O

The O
extraordinary O
conservation O
of O
the O
PAX6 O
protein O
at O
the O
amino O
acid O
level O
amongst O
vertebrates O
predicts O
that O
pathological O
missense O
mutations O
should O
in O
fact O
be O
common O
even O
though O
they O
are O
hardly O
ever O
seen O
in O
aniridia B
patients O
. O

This O
indicates O
that O
there O
is O
a O
heavy O
ascertainment O
bias O
in O
the O
selection O
of O
patients O
for O
PAX6 O
mutation O
analysis O
and O
that O
the O
missing O
PAX6 O
missense O
mutations O
frequently O
may O
underlie O
phenotypes O
distinct O
from O
textbook O
aniridia I
. O

Here O
we O
present O
four O
novel O
PAX6 O
missense O
mutations O
, O
two O
in O
association O
with O
atypical O
phenotypes O
ectopia B
pupillae I
( O
displaced O
pupils O
) O
and O
congenital B
nystagmus I
( O
searching O
gaze O
) O
, O
and O
two O
in O
association O
with O
more O
recognizable O
aniridia B
phenotypes O
. O

Strikingly O
, O
all O
four O
mutations O
are O
located O
within O
the O
PAX6 O
paired O
domain O
and O
affect O
amino O
acids O
which O
are O
highly O
conserved O
in O
all O
known O
paired O
domain O
proteins O
. O

Our O
results O
support O
the O
hypothesis O
that O
the O
under O
- O
representation O
of O
missense O
mutations O
is O
caused O
by O
ascertainment O
bias O
and O
suggest O
that O
a O
substantial O
burden O
of O
PAX6 B
- I
related I
disease I
remains O
to O
be O
uncovered O
. O
. O

The O
chromosomal O
order O
of O
genes O
controlling O
the O
major O
histocompatibility O
complex O
, O
properdin O
factor O
B O
, O
and O
deficiency B
of I
the I
second I
component I
of I
complement I
. O

The O
relationship O
of O
the O
genes O
coding O
for O
HLA O
to O
those O
coding O
for O
properdin O
Factor O
B O
allotypes O
and O
for O
deficiency B
of I
the I
second I
component I
of I
complement I
( O
C2 O
) O
was O
studied O
in O
families O
of O
patients O
with O
connective B
tissue I
disorders I
. O

Patients O
were O
selected O
because O
they O
were O
heterozygous O
or O
homozygous O
for O
C2 B
deficiency I
. O

12 O
families O
with O
15 O
matings O
informative O
for O
C2 B
deficiency I
were O
found O
. O

Of O
57 O
informative O
meioses O
, O
two O
crossovers O
were O
noted O
between O
the O
C2 B
deficiency I
gene O
and O
the O
HLA O
- O
B O
gene O
, O
with O
a O
recombinant O
fraction O
of O
0 O
. O

035 O
. O

A O
lod O
score O
of O
13 O
was O
calculated O
for O
linkage O
between O
C2 B
deficiency I
and O
HLA O
- O
B O
at O
a O
maximum O
likelihood O
value O
of O
the O
recombinant O
fraction O
of O
0 O
. O

04 O
. O

18 O
families O
with O
21 O
informative O
matings O
for O
both O
properdin O
Factor O
B O
allotype O
and O
HLA O
- O
B O
were O
found O
. O

Of O
72 O
informative O
meioses O
, O
three O
recombinants O
were O
found O
, O
giving O
a O
recombinant O
fraction O
of O
0 O
. O

042 O
. O

A O
lod O
score O
of O
16 O
between O
HLA O
- O
B O
and O
Factor O
B O
allotypes O
was O
calculated O
at O
a O
maximum O
likelihood O
value O
of O
the O
recombinant O
fraction O
of O
0 O
. O

04 O
. O

A O
crossover O
was O
shown O
to O
have O
occurred O
between O
genes O
for O
Factor O
B O
and O
HLA O
- O
D O
, O
in O
which O
HLA O
- O
D O
segregared O
with O
HLA O
- O
A O
and O
B O
. O

These O
studies O
suggest O
that O
the O
genes O
for O
Factor O
B O
and O
C2 B
deficiency I
are O
located O
outside O
those O
for O
HLA O
, O
that O
the O
order O
of O
genese O
is O
HLA O
- O
A O
, O
- O
B O
, O
- O
D O
, O
Factor O
B O
allotype O
, O
C2 B
deficiency I
, O
that O
the O
genes O
coding O
for O
C2 B
deficiency I
and O
Factor O
B O
allotypes O
are O
approximately O
3 O
- O
- O
5 O
centimorgans O
from O
the O
HLA O
- O
A O
and O
HLA O
- O
B O
loci O
, O
and O
that O
the O
apparent O
lack O
of O
recombinants O
between O
the O
Factor O
B O
gene O
and O
C2 B
deficiency I
gene O
suggests O
that O
these O
two O
genes O
lie O
in O
close O
proximity O
to O
one O
another O
. O

Distribution O
of O
emerin O
and O
lamins O
in O
the O
heart O
and O
implications O
for O
Emery B
- I
Dreifuss I
muscular I
dystrophy I
. O

Emerin O
is O
a O
nuclear O
membrane O
protein O
which O
is O
missing O
or O
defective O
in O
Emery B
- I
Dreifuss I
muscular I
dystrophy I
( O
EDMD B
) O
. O

It O
is O
one O
member O
of O
a O
family O
of O
lamina O
- O
associated O
proteins O
which O
includes O
LAP1 O
, O
LAP2 O
and O
lamin O
B O
receptor O
( O
LBR O
) O
. O

A O
panel O
of O
16 O
monoclonal O
antibodies O
( O
mAbs O
) O
has O
been O
mapped O
to O
six O
specific O
sites O
throughout O
the O
emerin O
molecule O
using O
phage O
- O
displayed O
peptide O
libraries O
and O
has O
been O
used O
to O
localize O
emerin O
in O
human O
and O
rabbit O
heart O
. O

Several O
mAbs O
against O
different O
emerin O
epitopes O
did O
not O
recognize O
intercalated O
discs O
in O
the O
heart O
, O
though O
they O
recognized O
cardiomyocyte O
nuclei O
strongly O
, O
both O
at O
the O
rim O
and O
in O
intranuclear O
spots O
or O
channels O
. O

A O
polyclonal O
rabbit O
antiserum O
against O
emerin O
did O
recognize O
both O
nuclear O
membrane O
and O
intercalated O
discs O
but O
, O
after O
affinity O
purification O
against O
a O
pure O
- O
emerin O
band O
on O
a O
western O
blot O
, O
it O
stained O
only O
the O
nuclear O
membrane O
. O

These O
results O
would O
not O
be O
expected O
if O
immunostaining O
at O
intercalated O
discs O
were O
due O
to O
a O
product O
of O
the O
emerin O
gene O
and O
, O
therefore O
, O
cast O
some O
doubt O
upon O
the O
hypothesis O
that O
cardiac B
defects I
in O
EDMD B
are O
caused O
by O
absence O
of O
emerin O
from O
intercalated O
discs O
. O

Although O
emerin O
was O
abundant O
in O
the O
membranes O
of O
cardiomyocyte O
nuclei O
, O
it O
was O
absent O
from O
many O
non O
- O
myocyte O
cells O
in O
the O
heart O
. O

This O
distribution O
of O
emerin O
was O
similar O
to O
that O
of O
lamin O
A O
, O
a O
candidate O
gene O
for O
an O
autosomal O
form O
of O
EDMD B
. O

In O
contrast O
, O
lamin O
B1 O
was O
absent O
from O
cardiomyocyte O
nuclei O
, O
showing O
that O
lamin O
B1 O
is O
not O
essential O
for O
localization O
of O
emerin O
to O
the O
nuclear O
lamina O
. O

Lamin O
B1 O
is O
also O
almost O
completely O
absent O
from O
skeletal O
muscle O
nuclei O
. O

In O
EDMD B
, O
the O
additional O
absence O
of O
lamin O
B1 O
from O
heart O
and O
skeletal O
muscle O
nuclei O
which O
already O
lack O
emerin O
may O
offer O
an O
alternative O
explanation O
of O
why O
these O
tissues O
are O
particularly O
affected O
. O
. O

Genetic O
mapping O
of O
the O
copper B
toxicosis I
locus O
in O
Bedlington O
terriers O
to O
dog O
chromosome O
10 O
, O
in O
a O
region O
syntenic O
to O
human O
chromosome O
region O
2p13 O
- O
p16 O
. O

Abnormal B
hepatic I
copper I
accumulation I
is O
recognized O
as O
an O
inherited B
disorder I
in O
man O
, O
mouse O
, O
rat O
and O
dog O
. O

The O
major O
cause O
of O
hepatic B
copper I
accumulation I
in O
man O
is O
a O
dysfunctional O
ATP7B O
gene O
, O
causing O
Wilson B
disease I
( O
WD B
) O
. O

Mutations O
in O
the O
ATP7B O
genes O
have O
also O
been O
demonstrated O
in O
mouse O
and O
rat O
. O

The O
ATP7B O
gene O
has O
been O
excluded O
in O
the O
much O
rarer O
human O
copper B
overload I
disease I
non B
- I
Indian I
childhood I
cirrhosis I
, O
indicating O
genetic O
heterogeneity O
. O

By O
investigating O
the O
common O
autosomal B
recessive I
copper I
toxicosis I
( O
CT B
) O
in O
Bedlington O
terriers O
, O
we O
have O
identified O
a O
new O
locus O
involved O
in O
progressive B
liver I
disease I
. O

We O
examined O
whether O
the O
WD B
gene O
ATP7B O
was O
also O
causative O
for O
CT B
by O
investigating O
the O
chromosomal O
co O
- O
localization O
of O
ATP7B O
and O
C04107 O
, O
using O
fluorescence O
in O
situ O
hybridization O
( O
FISH O
) O
. O

C04107 O
is O
an O
anonymous O
microsatellite O
marker O
closely O
linked O
to O
CT O
. O

However O
, O
BAC O
clones O
containing O
ATP7B O
and O
C04107 O
mapped O
to O
the O
canine O
chromosome O
regions O
CFA22q11 O
and O
CFA10q26 O
, O
respectively O
, O
demonstrating O
that O
WD B
cannot O
be O
homologous O
to O
CT O
. O

The O
copper O
transport O
genes O
CTR1 O
and O
CTR2 O
were O
also O
excluded O
as O
candidate O
genes O
for O
CT O
since O
they O
both O
mapped O
to O
canine O
chromosome O
region O
CFA11q22 O
. O

2 O
- O
22 O
. O

5 O
. O

A O
transcribed O
sequence O
identified O
from O
the O
C04107 O
- O
containing O
BAC O
was O
found O
to O
be O
homologous O
to O
a O
gene O
expressed O
from O
human O
chromosome O
2p13 O
- O
p16 O
, O
a O
region O
devoid O
of O
any O
positional O
candidate O
genes O
. O

Molecular O
analysis O
of O
the O
APC B
gene O
in O
205 O
families O
: O
extended O
genotype O
- O
phenotype O
correlations O
in O
FAP B
and O
evidence O
for O
the O
role O
of O
APC B
amino O
acid O
changes O
in O
colorectal B
cancer I
predisposition O
. O

BACKGROUND O
/ O
AIMS O
The O
development O
of O
colorectal B
cancer I
and O
a O
variable O
range O
of O
extracolonic O
manifestations O
in O
familial B
adenomatous I
polyposis I
( O
FAP B
) O
is O
the O
result O
of O
the O
dominant O
inheritance O
of O
adenomatous B
polyposis I
coli I
( O
APC B
) O
gene O
mutations O
. O

In O
this O
study O
, O
direct O
mutation O
analysis O
of O
the O
APC B
gene O
was O
performed O
to O
determine O
genotype O
- O
phenotype O
correlations O
for O
nine O
extracolonic O
manifestations O
and O
to O
investigate O
the O
incidence O
of O
APC B
mutations O
in O
non B
- I
FAP I
colorectal I
cancer I
. O

METHODS O
The O
APC B
gene O
was O
analysed O
in O
190 O
unrelated O
FAP B
and O
15 O
non B
- I
FAP I
colorectal I
cancer I
patients O
using O
denaturing O
gradient O
gel O
electrophoresis O
, O
the O
protein O
truncation O
test O
, O
and O
direct O
sequencing O
. O

RESULTS O
Chain O
terminating O
signals O
were O
only O
identified O
in O
patients O
belonging O
to O
the O
FAP B
group O
( O
105 O
patients O
) O
. O

Amino O
acid O
changes O
were O
identified O
in O
four O
patients O
, O
three O
of O
whom O
belonged O
to O
the O
non O
- O
FAP O
group O
of O
colorectal B
cancer I
patients O
. O

Genotype O
- O
phenotype O
correlations O
identified O
significant O
differences O
in O
the O
nature O
of O
certain O
extracolonic O
manifestations O
in O
FAP B
patients O
belonging O
to O
three O
mutation O
subgroups O
. O

CONCLUSIONS O
Extended O
genotype O
- O
phenotype O
correlations O
made O
in O
this O
study O
may O
have O
the O
potential O
to O
determine O
the O
most O
appropriate O
surveillance O
and O
prophylactic O
treatment O
regimens O
for O
those O
patients O
with O
mutations O
associated O
with O
life O
threatening O
conditions O
. O

This O
study O
also O
provided O
evidence O
for O
the O
pathological O
nature O
of O
amino O
acid O
changes O
in O
APC B
associated O
with O
both O
FAP B
and I
non I
- I
FAP I
colorectal I
cancer I
patients O
. O
. O

Inherited B
colorectal I
polyposis I
and O
cancer B
risk O
of O
the O
APC B
I1307K O
polymorphism O
. O

Germ O
- O
line O
and O
somatic O
truncating O
mutations O
of O
the O
APC B
gene O
are O
thought O
to O
initiate O
colorectal B
tumor I
formation O
in O
familial B
adenomatous I
polyposis I
syndrome I
and O
sporadic O
colorectal I
carcinogenesis O
, O
respectively O
. O

Recently O
, O
an O
isoleucine O
- O
- O
> O
lysine O
polymorphism O
at O
codon O
1307 O
( O
I1307K O
) O
of O
the O
APC B
gene O
has O
been O
identified O
in O
6 O
% O
- O
7 O
% O
of O
the O
Ashkenazi O
Jewish O
population O
. O

To O
assess O
the O
risk O
of O
this O
common O
APC B
allelic O
variant O
in O
colorectal O
carcinogenesis O
, O
we O
have O
analyzed O
a O
large O
cohort O
of O
unselected O
Ashkenazi O
Jewish O
subjects O
with O
adenomatous B
polyps I
and O
. O
or O
colorectal B
cancer I
, O
for O
the O
APC B
I1307K O
polymorphism O
. O

The O
APC O
I1307K O
allele O
was O
identified O
in O
48 O
( O
10 O
. O
1 O
% O
) O
of O
476 O
patients O
. O

Compared O
with O
the O
frequency O
in O
two O
separate O
population O
control O
groups O
, O
the O
APC O
I1307K O
allele O
is O
associated O
with O
an O
estimated O
relative O
risk O
of O
1 O
. O

5 O
- O
1 O
. O

7 O
for O
colorectal B
neoplasia I
( O
both O
P O
= O
. O
01 O
) O
. O

Furthermore O
, O
compared O
with O
noncarriers O
, O
APC O
I1307K O
carriers O
had O
increased O
numbers O
of O
adenomas B
and O
colorectal B
cancers I
per O
patient O
( O
P O
= O
. O
03 O
) O
, O
as O
well O
as O
a O
younger O
age O
at O
diagnosis O
. O

We O
conclude O
that O
the O
APC O
I1307K O
variant O
leads O
to O
increased O
adenoma B
formation O
and O
directly O
contributes O
to O
3 O
% O
- O
4 O
% O
of O
all O
Ashkenazi O
Jewish O
colorectal B
cancer I
. O

The O
estimated O
relative O
risk O
for O
carriers O
may O
justify O
specific O
clinical O
screening O
for O
the O
360 O
, O
000 O
Americans O
expected O
to O
harbor O
this O
allele O
, O
and O
genetic O
testing O
in O
the O
setting O
of O
long O
- O
term O
- O
outcome O
studies O
may O
impact O
significantly O
on O
colorectal B
cancer I
prevention O
in O
this O
population O
. O

Localization O
of O
human O
BRCA1 O
and O
its O
loss O
in O
high O
- I
grade I
, I
non I
- I
inherited I
breast I
carcinomas I
. O

Although O
the O
link O
between O
the O
BRCA1 O
tumour B
- O
suppressor O
gene O
and O
hereditary B
breast I
and I
ovarian I
cancer I
is O
established O
, O
the O
role O
, O
if O
any O
, O
of O
BRCA1 O
in O
non B
- I
familial I
cancers I
is O
unclear O
. O

BRCA1 O
mutations O
are O
rare O
in O
sporadic B
cancers I
, O
but O
loss O
of O
BRCA1 O
resulting O
from O
reduced O
expression O
or O
incorrect O
subcellular O
localization O
is O
postulated O
to O
be O
important O
in O
non B
- I
familial I
breast I
and I
ovarian I
cancers I
. O

Epigenetic O
loss O
, O
however O
, O
has O
not O
received O
general O
acceptance O
due O
to O
controversy O
regarding O
the O
subcellular O
localization O
of O
BRCA1 O
proteins O
, O
reports O
of O
which O
have O
ranged O
from O
exclusively O
nuclear O
, O
to O
conditionally O
nuclear O
, O
to O
the O
ER O
/ O
golgi O
, O
to O
cytoplasmic O
invaginations O
into O
the O
nucleus O
. O

In O
an O
attempt O
to O
resolve O
this O
issue O
, O
we O
have O
comprehensively O
characterized O
19 O
anti O
- O
BRCA1 O
antibodies O
. O

These O
reagents O
detect O
a O
220 O
- O
kD O
protein O
localized O
in O
discrete O
nuclear O
foci O
in O
all O
epithelial O
cell O
lines O
, O
including O
those O
derived O
from O
breast B
malignancies I
. O

Immunohistochemical O
staining O
of O
human O
breast O
specimens O
also O
revealed O
BRCA1 O
nuclear O
foci O
in O
benign B
breast I
, I
invasive I
lobular I
cancers I
and O
low B
- I
grade I
ductal B
carcinomas I
. O

Conversely O
, O
BRCA1 O
expression O
was O
reduced O
or O
undetectable O
in O
the O
majority O
of O
high B
- I
grade I
, I
ductal I
carcinomas I
, O
suggesting O
that O
absence O
of O
BRCA1 O
may O
contribute O
to O
the O
pathogenesis O
of O
a O
significant O
percentage O
of O
sporadic B
breast I
cancers I
. O
. O