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DLHex-DGJ, a novel derivative of 1-deoxygalactonojirimycin with pharmacological chaperone activity in human G(M1)-gangliosidosis fibroblasts.
[gm1 gangliosidosis]
G
(
M
1
)
-
gangliosidosis
(
GM
1
)
and
Morquio
B
disease
(
MBD
)
are
rare
lysosomal
storage
disorders
caused
by
mutations
in
the
gene
GLB
1
.
Its
main
gene
product
,
human
acid
beta
-galactosidase
(
beta
-
Gal
)
degrades
two
functionally
important
molecules
,
G
(
M
1
)
-
ganglioside
and
keratan
sulfate
in
brain
and
connective
tissues
,
respectively
.
While
GM
1
is
a
severe
,
phenotypically
heterogenous
neurodegenerative
disorder
,
MBD
is
a
systemic
bone
disease
without
effects
on
the
central
nervous
system
.
A
MBD-
specific
mutation
,
p
.
W
273
L
,
was
shown
to
produce
stable
beta
-
Gal
precursors
,
normally
transported
and
processed
to
mature
,
intralysosomal
beta
-
Gal
.
In
accordance
with
the
MBD
phenotype
,
elevated
residual
activity
against
G
(
M
1
)
-
ganglioside
,
but
strongly
reduced
affinity
towards
keratan
sulfate
was
found
.
Most
GM
1
alleles
,
in
contrast
,
were
shown
to
affect
precursor
stability
and
intracellular
transport
.
Specific
alleles
,
p
.
R
201
C
and
p
.
R
201
H
result
in
misfolded
,
unstable
precursor
proteins
rapidly
degraded
by
endoplasmic
reticulum-associated
protein
degradation
(
ERAD
)
.
They
may
therefore
be
sensitive
to
stabilization
by
small
molecules
which
bind
at
the
active
site
and
provide
proper
conformation
.
Thus
the
stabilized
protein
may
escape
from
ERAD
processes
,
and
reach
the
lysosomes
in
an
active
state
,
as
proposed
for
enzyme
enhancement
therapy
(
EET
)
.
This
paper
demonstrates
that
a
novel
iminosugar
,
DLHex-DGJ
,
has
potent
effects
as
competitive
inhibitor
of
human
acid
beta
-galactosidase
in
vitro
,
and
describes
its
effects
on
activity
,
protein
expression
,
maturation
and
intracellular
transport
in
vivo
in
13
fibroblasts
lines
with
GLB
1
mutations
.
Beside
p
.
R
201
C
and
p
.
R
201
H
,
two
further
alleles
,
p
.
C
2
30
R
and
p
.
G
438
E
,
displayed
significant
sensitivity
against
DLHex-DGJ
,
with
an
increase
of
catalytic
activity
,
and
a
normalization
of
transport
and
lysosomal
processing
of
beta
-
Gal
precursors
.
Diseases
Validation
Diseases presenting
"specific mutation"
symptom
dystrophic epidermolysis bullosa
epidermolysis bullosa simplex
familial hypocalciuric hypercalcemia
gm1 gangliosidosis
junctional epidermolysis bullosa
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