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Multiple mechanisms of action of pyridoxine in primary hyperoxaluria type 1.
[primary hyperoxaluria type 1]
Primary
hyperoxaluria
type
1
(
PH
1
)
is
a
rare
hereditary
calcium
oxalate
kidney
stone
disease
caused
by
a
deficiency
of
the
liver
-
specific
pyridoxal-phosphate-dependent
peroxisomal
enzyme
alanine
:
glyoxylate
aminotransferase
(
AGT
)
.
About
one
third
of
patients
are
responsive
to
pharmacological
doses
of
pyridoxine
(
vitamin
B
6
)
,
but
its
mechanism
of
action
is
unknown
.
Using
stably
transformed
Chinese
Hamster
Ovary
(
CHO
)
cells
expressing
various
normal
and
mutant
forms
of
AGT
,
we
have
shown
that
pyridoxine
increases
the
net
expression
,
catalytic
activity
and
peroxisomal
import
of
the
most
common
mistargeted
mutant
form
of
AGT
(
i
.
e
.
Gly
170
Arg
on
the
background
of
the
polymorphic
minor
allele
)
.
These
multiple
effects
explain
for
the
first
time
the
action
of
pyridoxine
in
the
most
common
group
of
responsive
patients
.
Partial
effects
of
pyridoxine
were
also
observed
for
two
other
common
AGT
mutants
on
the
minor
allele
(
i
.
e
.
Phe
152
Ile
and
Ile
244
Thr
)
but
not
for
the
minor
allele
mutant
AGT
containing
a
Gly
41
A
rg
replacement
.
These
findings
demonstrate
that
pyridoxine
,
which
is
metabolised
to
pyridoxal
phosphate
,
the
essential
cofactor
of
AGT
,
achieves
its
effects
both
as
a
prosthetic
group
(
increasing
enzyme
catalytic
activity
)
and
a
chemical
chaperone
(
increasing
peroxisome
targeting
and
net
expression
)
.
This
new
understanding
should
aid
the
development
of
pharmacological
treatments
that
attempt
to
enhance
efficacy
of
pyridoxine
in
PH
1
,
as
well
as
encouraging
a
re
-evaluation
of
the
extent
of
pyridoxine
responsiveness
in
PH
1
,
as
more
patients
than
previously
thought
might
benefit
from
such
treatment
.
Diseases
Validation
Diseases presenting
"first time"
symptom
achondroplasia
acute rheumatic fever
adrenal incidentaloma
adrenomyeloneuropathy
alpha-thalassemia
aniridia
aromatase deficiency
canavan disease
carcinoma of the gallbladder
cholangiocarcinoma
classical phenylketonuria
congenital adrenal hyperplasia
congenital toxoplasmosis
cowden syndrome
cushing syndrome
cutaneous mastocytosis
dedifferentiated liposarcoma
dentin dysplasia
dentinogenesis imperfecta
dracunculiasis
dystrophic epidermolysis bullosa
epidermolysis bullosa simplex
erdheim-chester disease
erythropoietic protoporphyria
esophageal adenocarcinoma
esophageal carcinoma
esophageal squamous cell carcinoma
fabry disease
familial mediterranean fever
gm1 gangliosidosis
harlequin ichthyosis
heparin-induced thrombocytopenia
hirschsprung disease
hodgkin lymphoma, classical
holt-oram syndrome
hydrocephalus with stenosis of the aqueduct of sylvius
junctional epidermolysis bullosa
kabuki syndrome
kallmann syndrome
liposarcoma
locked-in syndrome
lymphangioleiomyomatosis
malignant atrophic papulosis
megacystis-microcolon-intestinal hypoperistalsis syndrome
monosomy 21
neuralgic amyotrophy
oculocutaneous albinism
oligodontia
omenn syndrome
oral submucous fibrosis
papillon-lefèvre syndrome
pendred syndrome
phenylketonuria
primary effusion lymphoma
primary hyperoxaluria type 1
severe combined immunodeficiency
sneddon syndrome
triple a syndrome
trochlear dysplasia
von hippel-lindau disease
waldenström macroglobulinemia
well-differentiated liposarcoma
werner syndrome
wiskott-aldrich syndrome
wolf-hirschhorn syndrome
x-linked adrenoleukodystrophy
zellweger syndrome
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