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A novel syndrome caused by the E410K amino acid substitution in the neuronal β-tubulin isotype 3.
[kallmann syndrome]
Missense
mutations
in
TUBB
3
,
the
gene
that
encodes
the
neuronal
-
specific
protein
β-tubulin
isotype
3
,
can
cause
isolated
or
syndromic
congenital
fibrosis
of
the
extraocular
muscles
,
a
form
of
complex
congenital
strabismus
characterized
by
cranial
nerve
misguidance
.
One
of
the
eight
TUBB
3
mutations
reported
to
cause
congenital
fibrosis
of
the
extraocular
muscles
,
c
.
1228
G
>
A
results
in
a
TUBB
3
E
410
K
amino
acid
substitution
that
directly
alters
a
kinesin
motor
protein
binding
site
.
We
report
the
detailed
phenotypes
of
eight
unrelated
individuals
who
harbour
this
de
novo
mutation
,
and
thus
define
the
'
TUBB
3
E
410
K
syndrome
'
.
Individuals
harbouring
this
mutation
were
previously
reported
to
have
congenital
fibrosis
of
the
extraocular
muscles
,
facial
weakness
,
developmental
delay
and
possible
peripheral
neuropathy
.
We
now
confirm
by
electrophysiology
that
a
progressive
sensorimotor
polyneuropathy
does
indeed
segregate
with
the
mutation
,
and
expand
the
TUBB
3
E
410
K
phenotype
to
include
Kallmann
syndrome
(
hypogonadotropic
hypogonadism
and
anosmia
)
,
stereotyped
midface
hypoplasia
,
intellectual
disabilities
and
,
in
some
cases
,
vocal
cord
paralysis
,
tracheomalacia
and
cyclic
vomiting
.
Neuroimaging
reveals
a
thin
corpus
callosum
and
anterior
commissure
,
and
hypoplastic
to
absent
olfactory
sulci
,
olfactory
bulbs
and
oculomotor
and
facial
nerves
,
which
support
underlying
abnormalities
in
axon
guidance
and
maintenance
.
Thus
,
the
E
410
K
substitution
defines
a
new
genetic
aetiology
for
Moebius
syndrome
,
Kallmann
syndrome
and
cyclic
vomiting
.
Moreover
,
the
c
.
1228
G
>
A
mutation
was
absent
in
DNA
from
∼
600
individuals
who
had
either
Kallmann
syndrome
or
isolated
or
syndromic
ocular
and
/
or
facial
dysmotility
disorders
,
but
who
did
not
have
the
combined
features
of
the
TUBB
3
E
410
K
syndrome
,
highlighting
the
specificity
of
this
phenotype-genotype
correlation
.
The
definition
of
the
TUBB
3
E
410
K
syndrome
will
allow
clinicians
to
identify
affected
individuals
and
predict
the
mutation
based
on
clinical
features
alone
.
Diseases
Validation
Diseases presenting
"detailed phenotypes of eight unrelated individuals who harbour"
symptom
kallmann syndrome
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