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Patients with Griscelli syndrome and normal pigmentation identify RAB27A mutations that selectively disrupt MUNC13-4 binding.
[oculocutaneous albinism]
Familial
hemophagocytic
lymphohistiocytosis
(
FHL
)
is
a
rare
and
often
fatal
disorder
characterized
by
defective
cellular
cytotoxicity
and
hyperinflammation
,
and
the
only
cure
known
to
date
is
hematopoietic
stem
cell
transplantation
.
Mutations
in
RAB
27
A
,
LYST
,
and
AP
3
B
1
give
rise
to
FHL
associated
with
oculocutaneous
albinism
,
and
patients
with
FHL
are
usually
only
screened
for
mutations
in
these
genes
when
albinism
is
observed
.
A
number
of
patients
with
FHL
and
normal
pigmentation
remain
without
a
genetic
diagnosis
.
We
asked
whether
patients
with
FHL
with
immunodeficiency
but
with
normal
pigmentation
might
sometimes
have
mutations
that
affected
cellular
cytotoxicity
without
affecting
pigmentation
.
We
carried
out
mutation
analysis
of
RAB
27
A
,
LYST
,
and
AP
3
B
1
in
patients
with
FHL
with
pigment
dilution
,
as
well
as
a
cohort
with
no
clinical
evidence
of
pigment
dilution
but
no
mutations
in
the
other
known
FHL-related
genes
(
PRF
1
,
STXBP
2
,
and
UNC
13
D
)
.
We
identify
patients
with
Griscelli
syndrome
type
2
with
biallelic
mutations
in
RAB
27
A
in
the
absence
of
albinism
.
All
6
patients
carried
mutations
at
amino
acids
R
141
,
Y
159
,
or
S
163
of
Rab
27
a
that
disrupt
the
interaction
of
Rab
27
a
with
Munc
13
-
4
,
without
impairing
the
interaction
between
melanophilin
and
Rab
27
a
.
These
studies
highlight
the
need
for
RAB
27
A
sequencing
in
patients
with
FHL
with
normal
pigmentation
and
identify
a
critical
binding
site
for
Munc
13
-
4
on
Rab
27
a
,
revealing
the
molecular
basis
of
this
interaction
.
Diseases
Validation
Diseases presenting
"pigmentation"
symptom
aniridia
congenital adrenal hyperplasia
congenital toxoplasmosis
cushing syndrome
epidermolysis bullosa simplex
erythropoietic protoporphyria
gm1 gangliosidosis
hirschsprung disease
homocystinuria without methylmalonic aciduria
junctional epidermolysis bullosa
kallmann syndrome
kindler syndrome
oculocutaneous albinism
oral submucous fibrosis
phenylketonuria
proteus syndrome
wiskott-aldrich syndrome
This symptom has already been validated