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Mutations in FGF17, IL17RD, DUSP6, SPRY4, and FLRT3 are identified in individuals with congenital hypogonadotropic hypogonadism.
[kallmann syndrome]
Congenital
hypogonadotropic
hypogonadism
(
CHH
)
and
its
anosmia
-associated
form
(
Kallmann
syndrome
[
KS
]
)
are
genetically
heterogeneous
.
Among
the
>
15
genes
implicated
in
these
conditions
,
mutations
in
FGF
8
and
FGFR
1
account
for
~
12
%
of
cases
;
notably
,
KAL
1
and
HS
6
ST
1
are
also
involved
in
FGFR
1
signaling
and
can
be
mutated
in
CHH
.
We
therefore
hypothesized
that
mutations
in
genes
encoding
a
broader
range
of
modulators
of
the
FGFR
1
pathway
might
contribute
to
the
genetics
of
CHH
as
causal
or
modifier
mutations
.
Thus
,
we
aimed
to
(
1
)
investigate
whether
CHH
individuals
harbor
mutations
in
members
of
the
so
-called
"
FGF
8
synexpression
"
group
and
(
2
)
validate
the
ability
of
a
bioinformatics
algorithm
on
the
basis
of
protein-protein
interactome
data
(
interactome-based
affiliation
scoring
[
IBAS
]
)
to
identify
high
-quality
candidate
genes
.
On
the
basis
of
sequence
homology
,
expression
,
and
structural
and
functional
data
,
seven
genes
were
selected
and
sequenced
in
386
unrelated
CHH
individuals
and
155
controls
.
Except
for
FGF
18
and
SPRY
2
,
all
other
genes
were
found
to
be
mutated
in
CHH
individuals
:
FGF
17
(
n
=
3
individuals
)
,
IL
17
RD
(
n
=
8
)
,
DUSP
6
(
n
=
5
)
,
SPRY
4
(
n
=
14
)
,
and
FLRT
3
(
n
=
3
)
.
Independently
,
IBAS
predicted
FGF
17
and
IL
17
RD
as
the
two
top
candidates
in
the
entire
proteome
on
the
basis
of
a
statistical
test
of
their
protein-protein
interaction
patterns
to
proteins
known
to
be
altered
in
CHH
.
Most
of
the
FGF
17
and
IL
17
RD
mutations
altered
protein
function
in
vitro
.
IL
17
RD
mutations
were
found
only
in
KS
individuals
and
were
strongly
linked
to
hearing
loss
(
6
/
8
individuals
)
.
Mutations
in
genes
encoding
components
of
the
FGF
pathway
are
associated
with
complex
modes
of
CHH
inheritance
and
act
primarily
as
contributors
to
an
oligogenic
genetic
architecture
underlying
CHH
.
Diseases
Validation
Diseases presenting
"complex modes of chh inheritance"
symptom
kallmann syndrome
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