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Variations in PROKR2, but not PROK2, are associated with hypopituitarism and septo-optic dysplasia.
[kallmann syndrome]
Loss
-of-function
mutations
in
PROK
2
and
PROKR
2
have
been
implicated
in
Kallmann
syndrome
(
KS
)
,
characterized
by
hypogonadotropic
hypogonadism
and
anosmia
.
Recent
data
suggest
overlapping
phenotypes
/
genotypes
between
KS
and
congenital
hypopituitarism
(
CH
)
,
including
septo-
optic
dysplasia
(
SOD
)
.
We
screened
a
cohort
of
patients
with
complex
forms
of
CH
(
n
=
422
)
for
mutations
in
PROK
2
and
PROKR
2
.
We
detected
5
PROKR
2
variants
in
11
patients
with
SOD
/
CH
:
novel
p
.
G
371
R
and
previously
reported
p
.
A
51
T
,
p
.
R
85
L
,
p
.
L
173
R
,
and
p
.
R
268
C-
the
latter
3
being
known
functionally
deleterious
variants
.
Surprisingly
,
1
patient
with
SOD
was
heterozygous
for
the
p
.
L
173
R
variant
,
whereas
his
phenotypically
unaffected
mother
was
homozygous
for
the
variant
.
We
sought
to
clarify
the
role
of
PROKR
2
in
hypothalamopituitary
development
through
analysis
of
Prokr
2
(
-
/
-
)
mice
.
Interestingly
,
these
revealed
predominantly
normal
hypothalamopituitary
development
and
terminal
cell
differentiation
,
with
the
exception
of
reduced
LH
;
this
was
inconsistent
with
patient
phenotypes
and
more
analogous
to
the
healthy
mother
,
although
she
did
not
have
KS
,
unlike
the
Prokr
2
(
-
/
-
)
mice
.
The
role
of
PROKR
2
in
the
etiology
of
CH
,
SOD
,
and
KS
is
uncertain
,
as
demonstrated
by
no
clear
phenotype-genotype
correlation
;
loss
-of-function
variants
in
heterozygosity
or
homozygosity
can
be
associated
with
these
disorders
.
However
,
we
report
a
phenotypically
normal
parent
,
homozygous
for
p
.
L
173
R
.
Our
data
suggest
that
the
variants
identified
herein
are
unlikely
to
be
implicated
in
isolation
in
these
disorders
;
other
genetic
or
environmental
modifiers
may
also
impact
on
the
etiology
.
Given
the
phenotypic
variability
,
genetic
counseling
may
presently
be
inappropriate
.
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