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Identification and characterization of 15 novel GALC gene mutations causing Krabbe disease.
[krabbe disease]
The
characterization
of
the
underlying
GALC
gene
lesions
was
performed
in
30
unrelated
patients
affected
by
Krabbe
disease
,
an
autosomal
recessive
leukodystrophy
caused
by
the
deficiency
of
lysosomal
enzyme
galactocerebrosidase
.
The
GALC
mutational
spectrum
comprised
33
distinct
mutant
(
including
15
previously
unreported
)
alleles
.
With
the
exception
of
4
novel
missense
mutations
that
replaced
evolutionarily
highly
conserved
residues
(
p
.
P
318
R
,
p
.
G
323
R
,
p
.
I
384
T
,
p
.
Y
490
N
)
,
most
of
the
newly
described
lesions
altered
mRNA
processing
.
These
included
7
frameshift
mutations
(
c
.
61
delG
,
c
.
408
delA
,
c
.
521
delA
,
c
.
1171
_
1175
delCATTCinsA
,
c
.
1405
_
1407
delCTCinsT
,
c
.
302
_
308
dupAAATAGG
,
c
.
1819
_
1826
dupGTTACAGG
)
,
3
nonsense
mutations
(
p
.
R
69
X
,
p
.
K
88
X
,
p
.
R
127
X
)
one
of
which
(
p
.
K
88
X
)
mediated
the
skipping
of
exon
2
,
and
a
splicing
mutation
(
c
.
1489
+
1
G
>
A
)
which
induced
the
partial
skipping
of
exon
13
.
In
addition
,
6
previously
unreported
GALC
polymorphisms
were
identified
.
The
functional
significance
of
the
novel
GALC
missense
mutations
and
polymorphisms
was
investigated
using
the
MutPred
analysis
tool
.
This
study
,
reporting
one
of
the
largest
genotype-phenotype
analyses
of
the
GALC
gene
so
far
performed
in
a
European
Krabbe
disease
cohort
,
revealed
that
the
Italian
GALC
mutational
profile
differs
significantly
from
other
populations
of
European
origin
.
This
is
due
in
part
to
a
GALC
missense
substitution
(
p
.
G
553
R
)
that
occurs
at
high
frequency
on
a
common
founder
haplotype
background
in
patients
originating
from
the
Naples
region
.
Diseases
Validation
Diseases presenting
"leukodystrophy"
symptom
achondroplasia
adrenomyeloneuropathy
alexander disease
cadasil
canavan disease
carcinoma of the gallbladder
classical phenylketonuria
coats disease
fabry disease
gm1 gangliosidosis
krabbe disease
neonatal adrenoleukodystrophy
phenylketonuria
pyruvate dehydrogenase deficiency
wiskott-aldrich syndrome
x-linked adrenoleukodystrophy
zellweger syndrome
This symptom has already been validated