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Molecular mechanism of a temperature-sensitive phenotype in peroxisomal biogenesis disorder.
[neonatal adrenoleukodystrophy]
Peroxisomal
biogenesis
disorders
include
Zellweger
syndrome
and
milder
phenotypes
,
such
as
neonatal
adrenoleukodystrophy
(
NALD
)
.
Our
previous
study
of
a
NALD
patient
with
a
marked
deterioration
by
a
fever
revealed
a
mutation
(
Ile
326
Thr
)
within
a
SH
3
domain
of
PEX
13
protein
(
Pex
13
p
)
,
showing
a
temperature-sensitive
(
TS
)
phenotype
in
peroxisomal
biogenesis
.
Clinical
TS
phenotypes
also
have
been
reported
in
several
genetic
diseases
,
but
the
molecular
mechanisms
still
remain
to
be
clarified
.
The
immunofluorescent
staining
with
anti-
Pex
13
p
antibody
also
revealed
TS
phenotype
of
the
I
326
T
mutant
protein
itself
in
the
patient
cells
.
Protease
digestion
of
the
recombinant
Pex
13
p
-
SH
3
domain
showed
an
increase
of
protease
susceptibility
,
suggesting
a
problem
of
mutant
protein
fold
.
Conformational
analyses
against
urea
denaturation
using
urea
gradient
gel
electrophoresis
or
fluorescence
emission
from
tryptophan
residue
revealed
that
the
mutant
protein
should
be
easily
unfolded
.
Far-
UV
circular
dichroism
(
CD
)
spectra
demonstrated
that
both
wild-
type
and
the
mutant
protein
have
antiparallel
beta
-sheets
as
their
secondary
structure
with
slightly
different
extent
.
The
thermal
unfolding
profiles
measured
by
CD
showed
a
marked
lower
melting
temperature
for
I
326
T
protein
compared
with
that
of
wild-
type
protein
.
Analysis
of
the
protein
3
D-
structure
indicated
that
the
Ile
326
should
be
a
core
residue
for
folding
kinetics
and
the
substitution
of
Ile
326
by
threonine
should
directly
alter
the
kinetic
equilibrium
,
suggesting
a
marked
increase
of
the
unfolded
molecules
when
the
patient
had
a
high
fever
.
Structural
analyses
of
the
protein
in
the
other
genetic
diseases
could
provide
an
avenue
for
better
understanding
of
genotype-phenotype
correlations
.
Diseases
Validation
Diseases presenting
"secondary structure"
symptom
epidermolysis bullosa simplex
hereditary cerebral hemorrhage with amyloidosis
inclusion body myositis
legionellosis
neonatal adrenoleukodystrophy
oculocutaneous albinism
pyruvate dehydrogenase deficiency
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