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

Hum. Mutat.2017 Jan;38(1):39-42. doi:10.1002/humu.23116. Epub 2016 Sep 21
Maki Igarashi 1 , Kei Takasawa 2 , Akiko Hakoda 3 , Junko Kanno 3 , Shuji Takada 4 , Mami Miyado 1 , Takashi Baba 5 , Ken-Ichirou Morohashi 5 , Toshihiro Tajima 6 , Kenichiro Hata 7 , Kazuhiko Nakabayashi 7 , Yoichi Matsubara 8 , Ryohei Sekido 9 , Tsutomu Ogata 10 , Kenichi Kashimada 2 , Maki Fukami 1
Maki Igarashi 1 , Kei Takasawa 2 , Akiko Hakoda 3 , Junko Kanno 3 , Shuji Takada 4 , Mami Miyado 1 , Takashi Baba 5 , Ken-Ichirou Morohashi 5 , Toshihiro Tajima 6 , Kenichiro Hata 7 , Kazuhiko Nakabayashi 7 , Yoichi Matsubara 8 , Ryohei Sekido 9 , Tsutomu Ogata 10 , Kenichi Kashimada 2 , Maki Fukami 1
+ et al

[No authors listed]

Author information
  • 1 Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
  • 2 Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
  • 3 Department of Endocrinology, Miyagi Children's Hospital, Sendai, Japan.
  • 4 Department of Systems BioMedicine, National Research Institute for Child Health and Development, Tokyo, Japan.
  • 5 Department of Molecular Biology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
  • 6 Department of Pediatrics, Hokkaido University School of Medicine, Sapporo, Japan.
  • 7 Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan.
  • 8 National Research Institute for Child Health and Development, Tokyo, Japan.
  • 9 Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom.
  • 10 Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan.

摘要

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.

KEYWORDS: 46,XX ovotesticular DSD, 46,XX testicular DSD, NR0B1, NR5A1, SOX9

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