TY - JOUR
T1 - Genomic basis of aromatase excess syndrome
T2 - Recombination- and replication-Mediated rearrangements leading to CYP19A1 overexpression
AU - Fukami, Maki
AU - Tsuchiya, Takayoshi
AU - Vollbach, Heike
AU - Brown, Kristy A.
AU - Abe, Shuji
AU - Ohtsu, Shigeyuki
AU - Wabitsch, Martin
AU - Burger, Henry
AU - Simpson, Evan R.
AU - Umezawa, Akihiro
AU - Shihara, Daizou
AU - Nakabayashi, Kazuhiko
AU - Bulun, Serdar E.
AU - Shozu, Makio
AU - Ogata, Tsutomu
PY - 2013/12
Y1 - 2013/12
N2 - 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.
AB - 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.
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U2 - 10.1210/jc.2013-2520
DO - 10.1210/jc.2013-2520
M3 - Article
C2 - 24064691
AN - SCOPUS:84889861223
SN - 0021-972X
VL - 98
SP - E2013-E2021
JO - Journal of Clinical Endocrinology and Metabolism
JF - Journal of Clinical Endocrinology and Metabolism
IS - 12
ER -
