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Gene identification for the cblD defect of vitamin B12 metabolism.
[homocystinuria without methylmalonic aciduria]
Vitamin
B
12
(
cobalamin
)
is
an
essential
cofactor
in
several
metabolic
pathways
.
Intracellular
conversion
of
cobalamin
to
its
two
coenzymes
,
adenosylcobalamin
in
mitochondria
and
methylcobalamin
in
the
cytoplasm
,
is
necessary
for
the
homeostasis
of
methylmalonic
acid
and
homocysteine
.
Nine
defects
of
intracellular
cobalamin
metabolism
have
been
defined
by
means
of
somatic
complementation
analysis
.
One
of
these
defects
,
the
cblD
defect
,
can
cause
isolated
methylmalonic
aciduria
,
isolated
homocystinuria
,
or
both
.
Affected
persons
present
with
multisystem
clinical
abnormalities
,
including
developmental
,
hematologic
,
neurologic
,
and
metabolic
findings
.
The
gene
responsible
for
the
cblD
defect
has
not
been
identified
.
We
studied
seven
patients
with
the
cblD
defect
,
and
skin
fibroblasts
from
each
were
investigated
in
cell
culture
.
Microcell-mediated
chromosome
transfer
and
refined
genetic
mapping
were
used
to
localize
the
responsible
gene
.
This
gene
was
transfected
into
cblD
fibroblasts
to
test
for
the
rescue
of
adenosylcobalamin
and
methylcobalamin
synthesis
.
The
cblD
gene
was
localized
to
human
chromosome
2
q
23
.
2
,
and
a
candidate
gene
,
designated
MMADHC
(
methylmalonic
aciduria
,
cblD
type
,
and
homocystinuria
)
,
was
identified
in
this
region
.
Transfection
of
wild-
type
MMADHC
rescued
the
cellular
phenotype
,
and
the
functional
importance
of
mutant
alleles
was
shown
by
means
of
transfection
with
mutant
constructs
.
The
predicted
MMADHC
protein
has
sequence
homology
with
a
bacterial
ATP-binding
cassette
transporter
and
contains
a
putative
cobalamin
binding
motif
and
a
putative
mitochondrial
targeting
sequence
.
Mutations
in
a
gene
we
designated
MMADHC
are
responsible
for
the
cblD
defect
in
vitamin
B
12
metabolism
.
Various
mutations
are
associated
with
each
of
the
three
biochemical
phenotypes
of
the
disorder
.
Diseases
Validation
Diseases presenting
"methylmalonic aciduria"
symptom
canavan disease
homocystinuria without methylmalonic aciduria
This symptom has already been validated