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Functional consequences of AXL sequence variants in hypogonadotropic hypogonadism.
[kallmann syndrome]
Prior
studies
showed
that
Axl
/
Tyro
3
null
mice
have
delayed
first
estrus
and
abnormal
cyclicity
due
to
developmental
defects
in
GnRH
neuron
migration
and
survival
.
The
objective
of
the
study
was
to
test
whether
the
absence
of
Axl
would
alter
reproductive
function
in
mice
and
that
mutations
in
AXL
are
present
in
patients
with
Kallmann
syndrome
(
KS
)
or
normosmic
idiopathic
hypogonadotropic
hypogonadism
(
nIHH
)
.
The
sexual
maturation
of
Axl
null
mice
was
examined
.
The
coding
region
of
AXL
was
sequenced
in
104
unrelated
,
carefully
phenotyped
KS
or
nIHH
subjects
.
Frequency
of
mutations
was
compared
with
other
causes
of
GnRH
deficiency
.
Functional
assays
were
performed
on
the
detected
mutations
.
Axl
null
mice
demonstrated
delay
in
first
estrus
and
the
interval
between
vaginal
opening
and
first
estrus
.
Three
missense
AXL
mutations
(
p
.
L
50
F
,
p
.
S
202
C
,
and
p
.
Q
361
P
)
and
one
intronic
variant
6
bp
upstream
from
the
start
of
exon
5
(
c
.
586
-
6
C
>
T
)
were
identified
in
two
KS
and
2
two
nIHH
subjects
.
Comparison
of
the
frequencies
of
AXL
mutations
with
other
putative
causes
of
idiopathic
hypogonadotropic
hypogonadism
confirmed
they
are
rare
variants
.
Testing
of
the
c
.
586
-
6
C
>
T
mutation
revealed
no
abnormal
splicing
.
Surface
plasmon
resonance
analysis
of
the
p
.
L
50
F
,
p
.
S
202
C
,
and
p
.
Q
361
P
mutations
showed
no
altered
Gas
6
ligand
binding
.
In
contrast
,
GT
1
-
7
GnRH
neuronal
cells
expressing
p
.
S
202
C
or
p
.
Q
361
P
demonstrated
defective
ligand
dependent
receptor
processing
and
importantly
aberrant
neuronal
migration
.
In
addition
,
the
p
.
Q
361
P
showed
defective
ligand
independent
chemotaxis
.
Functional
consequences
of
AXL
sequence
variants
in
patients
with
idiopathic
hypogonadotropic
hypogonadism
support
the
importance
of
AXL
and
the
Tyro
3
,
Axl
,
Mer
(
TAM
)
family
in
reproductive
development
.