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Zebrafish tbx5 paralogs demonstrate independent essential requirements in cardiac and pectoral fin development.
[holt-oram syndrome]
T
-
box
genes
constitute
a
large
family
of
transcriptional
regulators
involved
in
developmental
patterning
.
Homozygous
mutation
of
tbx
5
leads
to
embryonic
lethal
cardiac
phenotypes
and
forelimb
malformations
in
vertebrate
models
.
Haploinsufficiency
of
tbx
5
results
in
Holt-
Oram
syndrome
,
a
human
congenital
disease
characterized
by
cardiac
and
forelimb
defects
.
Homozygous
mutation
of
zebrafish
tbx
5
a
leads
to
lethal
defects
in
cardiac
looping
morphogenesis
,
blocks
pectoral
fin
initiation
,
and
impairs
outgrowth
.
Recently
,
a
second
zebrafish
tbx
5
gene
was
described
,
termed
tbx
5
b
.
Our
phylogenetic
analyses
confirm
tbx
5
b
as
a
paralog
that
likely
arose
in
the
teleost-
specific
whole
genome
duplication
∼
270
MYA
.
Using
morpholino
depletion
studies
,
we
find
that
tbx
5
b
is
required
in
the
heart
for
embryonic
survival
,
and
influences
the
timing
and
morphogenesis
of
pectoral
fin
development
.
Because
tbx
5
a
hypomorphic
mutations
are
embryonic
lethal
,
tbx
5
a
and
tbx
5
b
functions
in
the
heart
must
not
be
completely
redundant
.
Consistent
with
this
hypothesis
,
simultaneous
depletion
of
both
tbx
5
paralogs
did
not
lead
to
more
severe
phenotypes
,
and
injection
of
wild-
type
mRNA
from
one
tbx
5
paralog
was
not
sufficient
to
cross-rescue
phenotypes
of
the
paralogous
gene
.
Collectively
,
these
data
indicate
that
,
despite
similar
spatio-
temporal
expression
patterns
,
tbx
5
a
and
tbx
5
b
have
independent
functions
in
heart
and
fin
development
.
Diseases
Validation
Diseases presenting
"large family"
symptom
cadasil
dentinogenesis imperfecta
fabry disease
holt-oram syndrome
kindler syndrome
monosomy 21
neuralgic amyotrophy
wiskott-aldrich syndrome
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