Rare Diseases Symptoms Automatic Extraction
Home
A random Abstract
Our Project
Our Team
Characterization of functional domains of the cblD (MMADHC) gene product.
[homocystinuria without methylmalonic aciduria]
In
humans
vitamin
B
12
(
cobalamin
,
Cbl
)
must
be
converted
into
two
coenzyme
forms
,
methylcobalamin
(
MeCbl
)
and
adenosylcobalamin
(
AdoCbl
)
,
in
order
to
maintain
intracellular
homeostasis
of
homocysteine
and
methylmalonic
acid
,
respectively
.
Previously
we
have
shown
that
in
cblD
patients
three
types
of
MMADHC
mutations
exist
:
1
)
null
mutations
N-
terminal
to
Met
116
cause
isolated
methylmalonic
aciduria
(
cblD-MMA
)
due
to
AdoCbl
deficiency
;
2
)
null
mutations
across
the
C-
terminus
(
p
.
Y
140
-
R
250
)
cause
combined
methylmalonic
aciduria
and
homocystinuria
(
cblD-MMA
/
HC
)
due
to
AdoCbl
and
MeCbl
deficiency
;
3
)
missense
mutations
in
a
conserved
C-
terminal
region
(
p
.
D
246
-
L
259
)
cause
isolated
homocystinuria
(
cblD-HC
)
due
to
MeCbl
deficiency
.
To
better
understand
the
domain
boundaries
related
to
MeCbl
formation
,
we
made
selected
point
mutations
and
C-
terminal
truncations
in
MMADHC
and
tested
rescue
of
MeCbl
and
AdoCbl
synthesis
in
immortalized
cblD-MMA
/
HC
patient
fibroblasts
.
Testing
20
mutations
(
15
missense
and
five
C-
terminal
truncations
)
across
p
.
P
154
-
S
287
revealed
the
presence
of
a
region
(
p
.
R
197
-
D
226
)
responsible
for
MeCbl
synthesis
,
which
gave
a
similar
cellular
phenotype
as
cblD-HC
.
Further
,
mutation
of
the
polypeptide
stretch
between
the
new
and
patient
defined
regions
(
p
.
D
226
-
D
246
)
and
directly
C-
terminal
to
the
patient
region
(
p
.
L
259
-
R
266
)
,
gave
cellular
phenotypes
intermediate
to
those
of
cblD-HC
and
cblD-MMA
/
HC
.
Finally
,
C-
terminal
truncation
of
more
than
20
amino
acids
resulted
in
a
cblD-MMA
/
HC
like
cellular
phenotype
,
while
truncation
of
between
ten
and
20
amino
acids
resulted
in
a
cblD-HC
like
cellular
phenotype
.
These
data
suggest
that
specific
regions
of
MMADHC
are
involved
in
differential
regulation
of
AdoCbl
and
MeCbl
synthesis
and
help
better
define
the
boundaries
of
these
regions
.
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