Identical NR5A1 Missense Mutations in Two Unrelated 46,XX Individuals with Testicular Tissues

Maki Igarashi, Kei Takasawa, Akiko Hakoda, Junko Kanno, Shuji Takada, Mami Miyado, Takashi Baba, Ken-Ichirou Morohashi, Toshihiro Tajima, Kenichiro Hata, Kazuhiko Nakabayashi, Yoichi Matsubara, Ryohei Sekido, Tsutomu Ogata, Kenichi Kashimada, Maki Fukami

Research output: Contribution to journalArticlepeer-review

38 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)39-42
Number of pages4
JournalHuman Mutation
Issue number1
Early online date21 Sept 2016
Publication statusPublished - 1 Jan 2017

Bibliographical note

Funded by Japan Society for the Promotion of Science. Grant Number: 26293224, Ministry of Education, Culture, Sports, Science and Technology, Ministry of Health, Labor and Welfare, the Japan Agency for Medical Research and Development, National Center for Child Health and Development (26-11), Takeda foundation.


  • NR0B1
  • NR5A1
  • SOX9
  • 46,XX ovotesticular DSD
  • 46,XX testicular DSD


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