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Aromatase deficiency in a Chinese adult man caused by novel compound heterozygous CYP19A1 mutations: Effects of estrogen replacement therapy on the bone, lipid, liver and glucose metabolism.
[aromatase deficiency]
Aromatase
deficiency
is
a
rare
disorder
resulting
in
estrogen
insufficiency
in
humans
.
It
has
been
reported
in
remarkably
few
men
with
loss
-of-function
mutations
in
the
CYP
19
A
1
gene
encoding
the
aromatase
,
a
cytochrome
P
450
enzyme
that
plays
a
crucial
role
in
the
biosynthesis
of
estrogens
from
androgens
.
We
investigated
a
non-consanguineous
family
including
an
adult
man
with
clinical
features
of
aromatase
deficiency
,
and
studied
the
effects
of
estrogen
replacement
in
the
man
.
We
investigated
the
clinical
and
biochemical
phenotype
,
performed
CYP
19
A
1
mutational
analysis
in
the
family
and
50
unrelated
persons
,
studied
the
effects
of
CYP
19
A
1
mutations
on
aromatase
protein
structure
,
functionally
characterized
the
mutations
by
cell-based
aromatase
activity
assays
,
and
studied
the
effects
of
estrogen
replacement
on
the
bone
,
lipid
,
liver
and
glucose
metabolism
.
The
man
with
clinical
features
of
aromatase
deficiency
had
novel
compound
heterozygous
CYP
19
A
1
mutations
(
Y
81
C
and
L
451
P
)
that
were
not
found
in
50
unrelated
persons
.
Three
-dimensional
modeling
predicted
that
Y
81
C
and
L
451
P
mutants
disrupted
protein
structure
.
Functional
studies
on
the
basis
of
in
vitro
expression
showed
that
Y
81
C
and
L
45
P
mutants
significantly
decreased
the
aromatase
activity
and
catalytic
efficiency
.
Estrogen
replacement
in
the
man
increased
bone
mineral
density
,
accelerated
bone
maturation
,
improved
lipid
profile
and
liver
steatosis
,
and
improved
glucose
levels
but
not
insulin
resistance
.
We
have
identified
two
novel
CYP
19
A
1
missense
mutations
in
an
aromatase-
deficient
man
.
Estrogen
replacement
in
the
man
shows
great
impact
on
recovering
the
impairments
in
the
bone
,
lipid
,
liver
and
glucose
metabolism
,
but
fails
to
improve
insulin
resistance
.
Diseases
Validation
Diseases presenting
"loss-of-function mutations"
symptom
achondroplasia
alpha-thalassemia
aromatase deficiency
child syndrome
cowden syndrome
dystrophic epidermolysis bullosa
epidermolysis bullosa simplex
erythropoietic protoporphyria
esophageal adenocarcinoma
familial hypocalciuric hypercalcemia
harlequin ichthyosis
hirschsprung disease
kallmann syndrome
kindler syndrome
lamellar ichthyosis
neonatal adrenoleukodystrophy
pendred syndrome
werner syndrome
x-linked adrenoleukodystrophy
This symptom has already been validated