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Lysosomal multienzymatic complex-related diseases: a genetic study among Portuguese patients.
[gm1 gangliosidosis]
The
functional
activity
of
lysosomal
enzymes
sialidase
,
β-galactosidase
and
N-
acetylaminogalacto-
6
-
sulfate-sulfatase
in
the
cell
depends
on
their
association
in
a
multienzyme
complex
with
cathepsin
A
.
Mutations
in
any
of
the
components
of
this
complex
result
in
functional
deficiency
thereby
causing
severe
lysosomal
storage
disorders
.
Here
,
we
report
the
molecular
defects
underlying
sialidosis
(
mutations
in
sialidase
;
gene
NEU
1
)
,
galactosialidosis
(
mutations
in
cathepsin
A
;
gene
PPGB
)
and
GM
1
gangliosidosis
(
mutations
in
β-galactosidase
;
gene
GLB
1
)
in
Portuguese
patients
.
We
performed
molecular
studies
of
the
PPGB
,
NEU
1
and
GLB
1
genes
in
biochemically
diagnosed
Portuguese
patients
.
Gene
expression
was
determined
and
the
effect
of
each
mutation
predicted
at
protein
levels
.
In
the
NEU
1
gene
,
we
found
three
novel
missense
mutations
(
p
.
P
200
L
,
p
.
D
234
N
and
p
.
Q
282
H
)
and
one
nonsense
mutation
(
p
.
R
341
X
)
.
In
the
PPGB
gene
,
we
identified
two
missense
mutations
,
one
novel
(
p
.
G
8
6
V
)
and
one
already
described
(
p
.
V
104
M
)
,
as
well
as
two
new
deletions
(
c
.
230
delC
and
c
.
991
-
992
delT
)
that
give
rise
to
non-
functional
proteins
.
We
also
present
the
first
molecular
evidence
of
a
causal
missense
mutation
localized
to
the
cathepsin
A
active
site
.
Finally
,
in
the
GLB
1
gene
,
we
found
six
different
mutations
,
all
of
them
previously
described
(
p
.
R
59
H
,
p
.
R
201
H
,
p
.
H
281
Y
,
p
.
W
527
X
,
c
.
1572
-
1577
InsG
and
c
.
845
-
846
delC
)
.
Seven
novel
mutations
are
reported
here
,
contributing
to
our
knowledge
of
the
mutational
spectrum
of
these
diseases
and
to
a
better
understanding
of
the
genetics
of
the
lysosomal
multienzymatic
complex
.
The
results
of
this
study
will
allow
carrier
detection
in
affected
families
and
prenatal
molecular
diagnosis
,
leading
to
the
improvement
of
genetic
counseling
.
Diseases
Validation
Diseases presenting
"mutations in cathepsin a"
symptom
gm1 gangliosidosis
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