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Genomic basis of aromatase excess syndrome: recombination- and replication-mediated rearrangements leading to CYP19A1 overexpression.
[aromatase deficiency]
Genomic
rearrangements
at
15
q
21
have
been
shown
to
cause
overexpression
of
CYP
19
A
1
and
resultant
aromatase
excess
syndrome
(
AEXS
)
.
However
,
mutation
spectrum
,
clinical
consequences
,
and
underlying
mechanisms
of
these
rearrangements
remain
to
be
elucidated
.
The
aim
of
the
study
was
to
clarify
such
unsolved
matters
.
We
characterized
six
new
rearrangements
and
investigated
clinical
outcome
and
local
genomic
environments
of
these
rearrangements
and
of
three
previously
reported
duplications
/
deletions
.
Novel
rearrangements
included
simple
duplication
involving
exons
1
-
10
of
CYP
19
A
1
and
simple
and
complex
rearrangements
that
presumably
generated
chimeric
genes
consisting
of
the
coding
region
of
CYP
19
A
1
and
promoter-associated
exons
of
neighboring
genes
.
Clinical
severities
were
primarily
determined
by
the
copy
number
of
CYP
19
A
1
and
the
property
of
the
fused
promoters
.
Sequences
at
the
fusion
junctions
suggested
nonallelic
homologous
recombination
,
nonhomologous
end-joining
,
and
replication-based
errors
as
the
underlying
mechanisms
.
The
breakpoint-flanking
regions
were
not
enriched
with
GC
content
,
palindromes
,
noncanonical
DNA
structures
,
or
known
rearrangement-associated
motifs
.
The
rearrangements
resided
in
early
-replicating
segments
.
T
hese
results
indicate
that
AEXS
is
caused
by
duplications
involving
CYP
19
A
1
and
simple
and
complex
rearrangements
that
presumably
lead
to
the
usage
of
cryptic
promoters
of
several
neighboring
genes
.
Our
data
support
the
notion
that
phenotypes
depend
on
the
dosage
of
CYP
19
A
1
and
the
characteristics
of
the
fused
promoters
.
Furthermore
,
we
show
that
the
rearrangements
in
AEXS
are
generated
by
both
recombination-
and
replication-mediated
mechanisms
,
independent
of
the
known
rearrangement-inducing
DNA
features
or
late
-replication
timing
.
Thus
,
AEXS
represents
a
unique
model
for
human
genomic
disorders
.
Diseases
Validation
Diseases presenting
"investigated clinical outcome and local genomic environments of these rearrangements"
symptom
aromatase deficiency
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