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Molecular basis for the Kallmann syndrome-linked fibroblast growth factor receptor mutation.
[kallmann syndrome]
Kallmann
syndrome
(
KS
)
is
a
developmental
disease
that
expresses
in
patients
as
hypogonadotropic
hypogonadism
and
anosmia
.
KS
is
commonly
associated
with
mutations
in
the
extracellular
D
2
domain
of
the
fibroblast
growth
factor
receptor
(
FGFR
)
.
In
this
study
,
for
the
first
time
,
the
molecular
basis
for
the
FGFR
associated
KS
mutation
(
A
168
S
)
is
elucidated
using
a
variety
of
biophysical
experiments
,
including
multidimensional
NMR
spectroscopy
.
Secondary
and
tertiary
structural
analysis
using
far
UV
circular
dichroism
,
fluorescence
and
limited
trypsin
digestion
assays
suggest
that
the
KS
mutation
induces
subtle
tertiary
structure
change
in
the
D
2
domain
of
FGFR
.
Results
of
isothermal
titration
calorimetry
experiments
show
the
KS
mutation
causes
a
10
-
fold
decrease
in
heparin
binding
affinity
and
also
a
complete
loss
in
ligand
(
FGF-
1
)
binding
.
(
1
)
H-
(
15
)
N
chemical
perturbation
data
suggest
that
complete
loss
in
the
ligand
(
FGF
)
binding
affinity
is
triggered
by
a
subtle
conformational
change
that
disrupts
crucial
structural
interactions
in
both
the
heparin
and
the
FGF
binding
sites
in
the
D
2
domain
of
FGFR
.
The
novel
findings
reported
in
this
study
are
expected
to
provide
valuable
clues
toward
a
complete
understanding
of
the
other
genetic
diseases
linked
to
mutations
in
the
FGFR
.
Diseases
Validation
Diseases presenting
"loss in the ligand"
symptom
kallmann syndrome
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