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Comparative functional analysis of two fibroblast growth factor receptor 1 (FGFR1) mutations affecting the same residue (R254W and R254Q) in isolated hypogonadotropic hypogonadism (IHH).
[kallmann syndrome]
FGFR
1
mutations
have
been
identified
in
both
Kallmann
syndrome
and
normosmic
HH
(
nIHH
)
.
To
date
,
few
mutations
in
the
FGFR
1
gene
have
been
structurally
or
functionally
characterized
in
vitro
to
identify
molecular
mechanisms
that
contribute
to
the
disease
pathogenesis
.
We
attempted
to
define
the
in
vitro
functionality
of
two
FGFR
1
mutants
(
R
254
W
and
R
254
Q
)
,
resulting
from
two
different
amino
acid
substitutions
of
the
same
residue
,
and
to
correlate
the
in
vitro
findings
to
the
patient
phenotypes
.
Two
unrelated
GnRH
deficient
probands
were
found
to
harbor
mutations
in
FGFR
1
(
R
254
W
and
R
254
Q
)
.
Mutant
signaling
activity
and
expression
levels
were
evaluated
in
vitro
and
compared
to
a
wild
type
(
WT
)
receptor
.
Signaling
activity
was
determined
by
a
FGF
2
/
FGFR
1
dependent
transcription
reporter
assay
.
Receptor
total
expression
levels
were
assessed
by
Western
blot
and
cell
surface
expression
was
measured
by
a
radiolabeled
antibody
binding
assay
.
The
R
254
W
maximal
receptor
signaling
capacity
was
reduced
by
45
%
(
p
<
0
.
01
)
while
R
254
Q
activity
was
not
different
from
WT
.
However
,
both
mutants
displayed
diminished
total
protein
expression
levels
(
40
and
30
%
reduction
relative
to
WT
,
respectively
)
,
while
protein
maturation
was
unaffected
.
Accordingly
,
cell
surface
expression
levels
of
the
mutant
receptors
were
also
significantly
reduced
(
35
%
p
<
0
.
01
and
15
%
p
<
0
.
05
,
respectively
)
.
The
p
.
R
254
W
and
p
.
R
254
Q
are
both
loss
-of-function
mutations
as
demonstrated
by
their
reduced
overall
and
cell
surface
expression
levels
suggesting
a
deleterious
effect
on
receptor
folding
and
stability
.
It
appears
that
a
tryptophan
substitution
at
R
254
is
more
disruptive
to
receptor
structure
than
the
more
conserved
glutamine
substitution
.
No
clear
correlation
between
the
severity
of
in
vitro
loss
-of-function
and
phenotypic
presentation
could
be
assigned
.
Diseases
Validation
Diseases presenting
"two different amino acid substitutions of the same residue"
symptom
kallmann syndrome
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