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Mutations in FEZF1 cause Kallmann syndrome.
[kallmann syndrome]
Gonadotropin-releasing
hormone
(
GnRH
)
neurons
originate
outside
the
CNS
in
the
olfactory
placode
and
migrate
into
the
CNS
,
where
they
become
integral
components
of
the
hypothalamic
-
pituitary
-
gonadal
(
HPG
)
axis
.
Disruption
of
this
migration
results
in
Kallmann
syndrome
(
KS
)
,
which
is
characterized
by
anosmia
and
pubertal
failure
due
to
hypogonadotropic
hypogonadism
.
Using
candidate
-
gene
screening
,
autozygosity
mapping
,
and
whole-exome
sequencing
in
a
cohort
of
30
individuals
with
KS
,
we
searched
for
genes
newly
associated
with
KS
.
We
identified
homozygous
loss
-of-function
mutations
in
FEZF
1
in
two
independent
consanguineous
families
each
with
two
affected
siblings
.
The
FEZF
1
product
is
known
to
enable
axons
of
olfactory
receptor
neurons
(
ORNs
)
to
penetrate
the
CNS
basal
lamina
in
mice
.
Because
a
subset
of
axons
in
these
tracks
is
the
migratory
pathway
for
GnRH
neurons
,
in
FEZF
1
deficiency
,
GnRH
neurons
also
fail
to
enter
the
brain
.
These
results
indicate
that
FEZF
1
is
required
for
establishment
of
the
central
component
of
the
HPG
axis
in
humans
.
Diseases
Validation
Diseases presenting
"loss-of-function mutations"
symptom
achondroplasia
alpha-thalassemia
aromatase deficiency
child syndrome
cowden syndrome
dystrophic epidermolysis bullosa
epidermolysis bullosa simplex
erythropoietic protoporphyria
esophageal adenocarcinoma
familial hypocalciuric hypercalcemia
harlequin ichthyosis
hirschsprung disease
kallmann syndrome
kindler syndrome
lamellar ichthyosis
neonatal adrenoleukodystrophy
pendred syndrome
werner syndrome
x-linked adrenoleukodystrophy
This symptom has already been validated