Genomic basis of aromatase excess syndrome: recombination- and replication-mediated rearrangements leading to CYP19A1 overexpression.
BACKGROUND
Genomic rearrangements at 15q21 have been shown to cause overexpression of CYP19A1 and resultant aromatase excess syndrome (AEXS). However, mutation spectrum, clinical consequences, and underlying mechanisms of these rearrangements remain to be elucidated.


OBJECTIVE
The aim of the study was to clarify such unsolved matters.


METHODS
We characterized six new rearrangements and investigated clinical outcome and local genomic environments of these rearrangements and of three previously reported duplications/deletions.


RESULTS
Novel rearrangements included simple duplication involving exons 1-10 of CYP19A1 and simple and complex rearrangements that presumably generated chimeric genes consisting of the coding region of CYP19A1 and promoter-associated exons of neighboring genes. Clinical severities were primarily determined by the copy number of CYP19A1 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.


CONCLUSIONS
These results indicate that AEXS is caused by duplications involving CYP19A1 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 CYP19A1 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.
MD, Department of Molecular Endocrinology, National Research Institute for Child Health and Development, 2-10-1 Ohkura, Setagaya, Tokyo 157-8535, Japan. fukami-m@ncchd.go.jp.
Maki
M
Fukami
Takayoshi
T
Tsuchiya
Heike
H
Vollbach
Kristy A
KA
Brown
Shuji
S
Abe
Shigeyuki
S
Ohtsu
Martin
M
Wabitsch
Henry
H
Burger
Evan R
ER
Simpson
Akihiro
A
Umezawa
Daizou
D
Shihara
Kazuhiko
K
Nakabayashi
Serdar E
SE
Bulun
Makio
M
Shozu
Tsutomu
T
Ogata
D058489:46, XX Disorders of Sex Development / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D000293:Adolescent; D000328:Adult; D001141:Aromatase / Q000096:biosynthesis / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D002648:Child; D004261:DNA Replication; D017353:Gene Deletion; D018628:Gene Dosage; D020440:Gene Duplication; D050939:Gene Fusion; D015321:Gene Rearrangement; D006177:Gynecomastia / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D007248:Infertility, Male / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D008661:Metabolism, Inborn Errors / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D011401:Promoter Regions, Genetic; D011995:Recombination, Genetic; D012720:Severity of Illness Index
D001141:Aromatase; C561410:CYP19A1 protein, human