Genomic Basis of Aromatase Excess Syndrome: Recombination- and Replication-Mediated Rearrangements Leading to CYP19A1 Overexpression
Autor: | Kristy A. Brown, Kazuhiko Nakabayashi, Shigeyuki Ohtsu, Shuji Abe, Martin Wabitsch, Serdar E. Bulun, Heike Vollbach, Tsutomu Ogata, Evan R. Simpson, Maki Fukami, Takayoshi Tsuchiya, Makio Shozu, Henry G. Burger, Daizou Shihara, Akihiro Umezawa |
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Jazyk: | angličtina |
Rok vydání: | 2013 |
Předmět: |
Adult
DNA Replication Male 46 XX Disorders of Sex Development Adolescent Endocrinology Diabetes and Metabolism Clinical Biochemistry Non-allelic homologous recombination Gene Dosage Context (language use) Chimeric gene Biology medicine.disease_cause Biochemistry Severity of Illness Index Endocrinology Aromatase Gene Duplication Gene duplication medicine Coding region Humans Child Promoter Regions Genetic Gene Infertility Male Genetics Gene Rearrangement Recombination Genetic Mutation JCEM Online: Advances in Genetics Biochemistry (medical) Gene rearrangement Gynecomastia Gene Fusion Gene Deletion Metabolism Inborn Errors |
Popis: | Context: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.Design, Setting, and 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. |
Databáze: | OpenAIRE |
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