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A novel CASR mutation associated with neonatal severe hyperparathyroidism transmitted as an autosomal recessive disorder.
[familial hypocalciuric hypercalcemia]
Neonatal
severe
primary
hyperparathyroidism
(
NSHPT
,
MIM
239200
)
is
most
often
an
isolated
disorder
that
is
due
to
biallelic
inactivating
mutations
in
the
CASR
,
the
gene
encoding
the
calcium
sensing
receptor
;
NSHPT
is
inherited
from
parents
with
familial
hypocalciuric
hypercalcemia
,
each
of
whom
has
one
mutated
CASR
allele
.
To
report
clinical
and
genetic
findings
in
a
brother
and
sister
with
NSHPT
due
to
a
novel
mutation
in
the
CASR
transmitted
as
an
autosomal
recessive
trait
and
to
examine
the
functional
effect
of
the
mutation
.
A
brother
and
sister
with
marked
hypercalcemia
due
to
NSHPT
were
identified
;
the
boy
also
had
craniosynostosis
requiring
surgical
repair
.
The
genotyping
of
the
CASR
in
both
children
and
their
parents
who
were
eucalcemic
and
normophosphatemic
was
undertaken
.
In
order
to
examine
the
significance
of
the
variant
CASR
identified
,
the
CASR
variant
was
expressed
in
vitro
and
examined
by
three
computer
computational
programs
[
PolyPhen
2
,
MutationTaster
,
Sorting
Intolerant
From
Tolerant
(
SIFT
)
]
designed
to
evaluate
the
effect
of
a
nucleotide
variant
on
the
structure
and
likely
functional
consequence
upon
the
protein
product
.
A
sequence
variant
in
the
CASR
was
identified
[
G
>
T
point
mutation
at
nucleotide
c
.
2303
in
exon
7
(
c
.
2303
G
>
T
)
resulting
in
the
replacement
of
glycine
by
valine
at
codon
768
(
p
.
Gly
768
Val
)
]
.
Two
copies
of
this
CASR
variant
were
present
in
the
genome
of
the
siblings
while
a
single
copy
of
the
CASR
variant
was
present
in
both
of
the
clinically
and
biochemically
normal
parents
,
a
pattern
of
transmission
consistent
with
autosomal
recessive
inheritance
of
NSHPT
in
this
family
.
When
expressed
in
HEK
293
cells
in
vitro
,
the
novel
Gly
768
V
al
variant
did
not
interfere
with
protein
generation
or
migration
to
the
cell
membrane
in
vitro
.
The
analysis
of
the
functional
effect
of
the
Gly
768
V
al
CASR
variant
by
the
PolyPhen
2
,
MutationTaster
,
and
Sorting
Intolerant
From
Tolerant
computer
programs
revealed
that
this
mutation
was
very
likely
to
be
deleterious
.
The
NSHPT
associated
with
biallelic
Gly
768
Val
mutations
of
the
CASR
in
two
siblings
with
severe
hypercalcemia
and
hyperparathyroidism
and
their
clinically
and
biochemically
normal
heterozygous
parents
was
transmitted
as
an
autosomal
recessive
disorder
in
this
family
.
Diseases
Validation
Diseases presenting
"severe hypercalcemia"
symptom
familial hypocalciuric hypercalcemia
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