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Hirschsprung-like disease is exacerbated by reduced de novo GMP synthesis.
[hirschsprung disease]
Hirschsprung
disease
(
HSCR
)
is
a
partially
penetrant
oligogenic
birth
defect
that
occurs
when
enteric
nervous
system
(
ENS
)
precursors
fail
to
colonize
the
distal
bowel
during
early
pregnancy
.
Genetic
defects
underlie
HSCR
,
but
much
of
the
variability
in
the
occurrence
and
severity
of
the
birth
defect
remain
unexplained
.
We
hypothesized
that
nongenetic
factors
might
contribute
to
disease
development
.
Here
we
found
that
mycophenolate
,
an
inhibitor
of
de
novo
guanine
nucleotide
biosynthesis
,
and
8
other
drugs
identified
in
a
zebrafish
screen
impaired
ENS
development
.
In
mice
,
mycophenolate
treatment
selectively
impaired
ENS
precursor
proliferation
,
delayed
precursor
migration
,
and
induced
bowel
aganglionosis
.
In
2
different
mouse
models
of
HSCR
,
addition
of
mycophenolate
increased
the
penetrance
and
severity
of
Hirschsprung-like
pathology
.
Mycophenolate
treatment
also
reduced
ENS
precursor
migration
as
well
as
lamellipodia
formation
,
proliferation
,
and
survival
in
cultured
enteric
neural
crest–derived
cells
.
Using
X-
inactivation
mosaicism
for
the
purine
salvage
gene
Hprt
,
we
found
that
reduced
ENS
precursor
proliferation
most
likely
causes
mycophenolate-induced
migration
defects
and
aganglionosis
.
To
the
best
of
our
knowledge
,
mycophenolate
is
the
first
medicine
identified
that
causes
major
ENS
malformations
and
Hirschsprung-like
pathology
in
a
mammalian
model
.
These
studies
demonstrate
a
critical
role
for
de
novo
guanine
nucleotide
biosynthesis
in
ENS
development
and
suggest
that
some
cases
of
HSCR
may
be
preventable
.
Diseases
Validation
Diseases presenting
"distal bowel"
symptom
hirschsprung disease
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