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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
"previously reported p"
symptom
kallmann syndrome
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