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SEMA3A, a gene involved in axonal pathfinding, is mutated in patients with Kallmann syndrome.
[kallmann syndrome]
Kallmann
syndrome
(
KS
)
associates
congenital
hypogonadism
due
to
gonadotropin-releasing
hormone
(
GnRH
)
deficiency
and
anosmia
.
The
genetics
of
KS
involves
various
modes
of
transmission
,
including
oligogenic
inheritance
.
Here
,
we
report
that
Nrp
1
(
sema
/
sema
)
mutant
mice
that
lack
a
functional
semaphorin-binding
domain
in
neuropilin-
1
,
an
obligatory
coreceptor
of
semaphorin-
3
A
,
have
a
KS
-like
phenotype
.
Pathohistological
analysis
of
these
mice
indeed
showed
abnormal
development
of
the
peripheral
olfactory
system
and
defective
embryonic
migration
of
the
neuroendocrine
GnRH
cells
to
the
basal
forebrain
,
which
results
in
increased
mortality
of
newborn
mice
and
reduced
fertility
in
adults
.
We
thus
screened
386
KS
patients
for
the
presence
of
mutations
in
SEMA
3
A
(
by
Sanger
sequencing
of
all
17
coding
exons
and
flanking
splice
sites
)
and
identified
nonsynonymous
mutations
in
24
patients
,
specifically
,
a
frameshifting
small
deletion
(
D
538
fsX
31
)
and
seven
different
missense
mutations
(
R
66
W
,
N
153
S
,
I
400
V
,
V
435
I
,
T
688
A
,
R
730
Q
,
R
733
H
)
.
All
the
mutations
were
found
in
heterozygous
state
.
Seven
mutations
resulted
in
impaired
secretion
of
semaphorin-
3
A
by
transfected
COS
-
7
cells
(
D
538
fsX
31
,
R
66
W
,
V
435
I
)
or
reduced
signaling
activity
of
the
secreted
protein
in
the
GN
11
cell
line
derived
from
embryonic
GnRH
cells
(
N
153
S
,
I
400
V
,
T
688
A
,
R
733
H
)
,
which
strongly
suggests
that
these
mutations
have
a
pathogenic
effect
.
Notably
,
mutations
in
other
KS
genes
had
already
been
identified
,
in
heterozygous
state
,
in
five
of
these
patients
.
Our
findings
indicate
that
semaphorin-
3
A
signaling
insufficiency
contributes
to
the
pathogenesis
of
KS
and
further
substantiate
the
oligogenic
pattern
of
inheritance
in
this
developmental
disorder
.
Diseases
Validation
Diseases presenting
"developmental disorder"
symptom
cohen syndrome
holt-oram syndrome
kabuki syndrome
kallmann syndrome
proteus syndrome
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