Genomic basis of aromatase excess syndrome: Recombination- and replication-Mediated rearrangements leading to CYP19A1 overexpression

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

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

17 Scopus citations


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,weshowthat the rearrangements inAEXSare generated by both recombination- and replication-mediated mechanisms, independent of theknown rearrangement-inducing DNA features or late-replication timing. Thus, AEXS represents a unique model for human genomic disorders.

Original languageEnglish (US)
Pages (from-to)E2013-E2021
JournalJournal of clinical endocrinology and metabolism
Issue number12
StatePublished - Dec 2013

ASJC Scopus subject areas

  • Biochemistry, medical
  • Endocrinology
  • Biochemistry
  • Clinical Biochemistry
  • Endocrinology, Diabetes and Metabolism


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