Identical NR5A1 Missense Mutations in Two Unrelated 46, XX Individuals with Testicular Tissues. Issue 1 (21st September 2016)

• Record Type: Journal Article
• Authors: Igarashi, Maki; Takasawa, Kei; Hakoda, Akiko; Kanno, Junko; Takada, Shuji; Miyado, Mami; Baba, Takashi; Morohashi, Ken‐ichirou; Tajima, Toshihiro; Hata, Kenichiro; Nakabayashi, Kazuhiko; Matsubara, Yoichi; Sekido, Ryohei; Ogata, Tsutomu; Kashimada, Kenichi; Fukami, Maki
• Is Part Of: Human mutation. Volume 38:Issue 1(2017)
• Page Start: 39
• Page End: 42
• Publication Date: 2016-09-21
• Subjects: NR0B1 -- NR5A1 -- SOX9 -- 46, XX ovotesticular DSD -- 46, XX testicular DSD; Human chromosome abnormalities -- Periodicals; Mutation (Biology) -- Periodicals; 616.04205
• DOI: 10.1002/humu.23116
• Languages: English
• ISSNs: 1059-7794

Abstract

Abstract : We detected identical mutations of NR5A1 (alias SF1/Ad4BP ) in two unrelated genetic females with testicular/ovotesticular tissues. The p.Arg92Trp substitution (the orange structure in the left panel) resides within the DNA binding domain of NR5A1. The results of this study raise the possibility that specific mutations in NR5A1 can switch the developmental process of 46, XX gonads toward testicular formation. ABSTRACT: The role of monogenic mutations in the development of 46, XX testicular/ovotesticular disorders of sex development (DSD) remains speculative. Although mutations in NR5A1 are known to cause 46, XY gonadal dysgenesis and 46, XX ovarian insufficiency, such mutations have not been implicated in testicular development of 46, XX gonads. Here, we identified identical NR5A1 mutations in two unrelated Japanese patients with 46, XX testicular/ovotesticular DSD. The p.Arg92Trp mutation was absent from the clinically normal mothers and from 200 unaffected Japanese individuals. In silico analyses scored p.Arg92Trp as probably pathogenic. In vitro assays demonstrated that compared with wild‐type NR5A1, the mutant protein was less sensitive to NR0B1‐induced suppression on the SOX9 enhancer element. Other sequence variants found in the patients were unlikely to be associated with the phenotype. The results raise the possibility that specific mutations in NR5A1 underlie testicular development in genetic females.