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Spectrum of mutations in MMACHC, allelic expression, and evidence for genotype-phenotype correlations.
[homocystinuria without methylmalonic aciduria]
Methylmalonic
aciduria
and
homocystinuria
,
cblC
type
,
is
a
rare
disorder
of
intracellular
vitamin
B
(
12
)
(
cobalamin
[
Cbl
]
)
metabolism
caused
by
mutations
in
the
MMACHC
gene
.
MMACHC
was
sequenced
from
the
gDNA
of
118
cblC
individuals
.
Eleven
novel
mutations
were
identified
,
as
well
as
23
mutations
that
were
observed
previously
.
Six
sequence
variants
capture
haplotype
diversity
in
individuals
across
the
MMACHC
interval
.
Genotype-phenotype
correlations
of
common
mutations
were
apparent
;
individuals
with
c
.
394
C
>
T
tend
to
present
with
late-onset
disease
whereas
patients
with
c
.
331
C
>
T
and
c
.
271
dupA
tend
to
present
in
infancy
.
Other
missense
variants
were
also
associated
with
late
-
or
early
-onset
disease
.
Allelic
expression
analysis
was
carried
out
on
human
cblC
fibroblasts
compound
heterozygous
for
different
combinations
of
mutations
including
c
.
271
dupA
,
c
.
331
C
>
T
,
c
.
394
C
>
T
,
and
c
.
482
G
>
A
.
The
early
-onset
c
.
271
dupA
mutation
was
consistently
underexpressed
when
compared
to
control
alleles
and
the
late-onset
c
.
394
C
>
T
and
c
.
482
G
>
A
mutations
.
The
early
-onset
c
.
331
C
>
T
mutation
was
also
underexpressed
when
compared
to
control
alleles
and
the
c
.
394
C
>
T
mutation
.
Levels
of
MMACHC
mRNA
transcript
in
cell
lines
homozygous
for
c
.
271
dupA
,
c
.
331
C
>
T
,
and
c
.
394
C
>
T
were
assessed
using
quantitative
real-time
RT-PCR
.
Cell
lines
homozygous
for
the
late
onset
c
.
394
C
>
T
mutation
had
significantly
higher
levels
of
transcript
when
compared
to
cell
lines
homozygous
for
the
early
-onset
mutations
.
Differential
or
preferential
MMACHC
transcript
levels
may
provide
a
clue
as
to
why
individuals
carrying
c
.
394
C
>
T
generally
present
later
in
life
.