ArticleThe Journal of clinical endocrinology and metabolism2013
Genomic basis of aromatase excess syndrome: recombination- and replication-mediated rearrangements leading to CYP19A1 overexpression.
Article in The Journal of clinical endocrinology and metabolism, 2013. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 27 citations in OpenAlex.
- Genome-wide association study for stayability at different calvings in Nellore beef cattle.BMC genomics · 2024Article
- Long term effects of aromatase inhibitor treatment in patients with aromatase excess syndrome.Frontiers in endocrinology · 2024Article
- Baseline estrogen levels in postmenopausal women participating in the MAP.3 breast cancer chemoprevention trial.Menopause (New York, N.Y.) · 2020Article
- Article
- Next generation sequencing and array-based comparative genomic hybridization for molecular diagnosis of pediatric endocrine disorders.Annals of pediatric endocrinology & metabolism · 2017Review
- Prepubertal unilateral gynecomastia: report of 2 cases.Journal of clinical research in pediatric endocrinology · 2014Article
- Gynaecomastia--pathophysiology, diagnosis and treatment.Nature reviews. Endocrinology · 2014Review
- Understanding the pathological manifestations of aromatase excess syndrome: lessons for clinical diagnosis.Expert review of endocrinology & metabolism · 2014Review
- Complex correlations: replication timing and mutational landscapes during cancer and genome evolution.Current opinion in genetics & development · 2014Review
- An aroma of complexity: how the unique genetics of aromatase (CYP19A1) explain diverse phenotypes from hens and hyenas to human gynecomastia, and testicular and other tumors.The Journal of clinical endocrinology and metabolism · 2013Article
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Authors and funding
15 authors at 6 institutions in 3 countries.
Funding
Abstract
contextGenomic 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.
objectiveThe aim of the study was to clarify such unsolved matters. DESIGN, SETTING, AND
methodsWe characterized six new rearrangements and investigated clinical outcome and local genomic environments of these rearrangements and of three previously reported duplications/deletions.
resultsNovel 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.
conclusionsThese 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.
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