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Subcellular location of MMACHC and MMADHC, two human proteins central to intracellular vitamin B(12) metabolism.
[homocystinuria without methylmalonic aciduria]
MMACHC
and
MMADHC
are
the
genes
responsible
for
cblC
and
cblD
defects
of
vitamin
B
(
12
)
metabolism
,
respectively
.
Patients
with
cblC
and
cblD
defects
present
with
various
combinations
of
methylmalonic
aciduria
(
MMA
)
and
homocystinuria
(
HC
)
.
Those
with
cblC
mutations
have
both
MMA
and
HC
whereas
cblD
patients
can
present
with
one
of
three
distinct
biochemical
phenotypes
:
isolated
MMA
,
isolated
HC
,
or
combined
MMA
and
HC
.
Based
on
the
subcellular
localization
of
these
enzymatic
pathways
it
is
thought
that
MMACHC
functions
in
the
cytoplasm
while
MMADHC
functions
downstream
of
MMACHC
in
both
the
cytoplasm
and
the
mitochondrion
.
In
this
study
we
determined
the
subcellular
location
of
MMACHC
and
MMADHC
by
immunofluorescence
and
subcellular
fractionation
.
We
show
that
MMACHC
is
cytoplasmic
while
MMADHC
is
both
mitochondrial
and
cytoplasmic
,
consistent
with
the
proposal
that
MMADHC
acts
as
a
branch
point
for
vitamin
B
(
12
)
delivery
to
the
cytoplasm
and
mitochondria
.
The
factors
that
determine
the
distribution
of
MMADHC
between
the
cytoplasm
and
mitochondria
remain
unknown
.
Functional
complementation
experiments
showed
that
retroviral
expression
of
the
GFP
tagged
constructs
rescued
all
biochemical
defects
in
cblC
and
cblD
fibroblasts
except
propionate
incorporation
in
cblD-MMA
cells
,
suggesting
that
the
endogenous
mutant
protein
interferes
with
the
function
of
the
transduced
wild
type
construct
.
Diseases
Validation
Diseases presenting
"homocystinuria"
symptom
adrenomyeloneuropathy
cohen syndrome
homocystinuria without methylmalonic aciduria
primary hyperoxaluria type 1
pyruvate dehydrogenase deficiency
This symptom has already been validated
