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

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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.

Original languageEnglish
Pages (from-to)39-42
Number of pages4
JournalHuman mutation
Volume38
Issue number1
DOIs
Publication statusPublished - Jan 1 2017

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All Science Journal Classification (ASJC) codes

  • Genetics
  • Genetics(clinical)

Cite this

Igarashi, M., Takasawa, K., Hakoda, A., Kanno, J., Takada, S., Miyado, M., ... Fukami, M. (2017). Identical NR5A1 Missense Mutations in Two Unrelated 46,XX Individuals with Testicular Tissues. Human mutation, 38(1), 39-42. https://doi.org/10.1002/humu.23116