Genomic Basis of Aromatase Excess Syndrome: Recombination- and Replication-Mediated Rearrangements Leading to CYP19A1 Overexpression
Year: 2013
Type: article
Abstract: 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.
DOI: 10.1210/jc.2013-2520
Authors: Maki Fukami, Takayoshi Tsuchiya, Heike Vollbach, Kristy A. Brown, Shuji Abe, Shigeyuki Ohtsu, Martin Wabitsch, Henry Burger, Evan R. Simpson, Akihiro Umezawa, Daizou Shihara, Kazuhiko Nakabayashi, Serdar E. Bulun, Makio Shozu, Tsutomu Ogata
Institutions: National Center For Child Health and Development, Dokkyo Medical University Saitama Medical Center, Universität Ulm, University Hospital Ulm, Monash Medical Centre, Hakodate Goryoukaku Hospital, Kitasato University, Northwestern University, Chiba University, Hamamatsu University, Hamamatsu University School of Medicine
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: bronze
Awards: Aromatase induces ovulation via a reduction of follicular androgen and its application for infertility treatment, Demonstration of Novel Brain Molecular Mechanisms Regulating Reproduction, Clarification of (epi)genetic mechanisms involved in the development of human imprinting disorders, G2934954685, Investigation for molecular basis of hypothalamo-pituitary-gonadal dysfunction, Progestogen prevents hypoxic-ischemic encephalopathy of neonatal rats, G7417264191
OpenAlex ID: W2114676909