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

doi:10.1002/humu.23116

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

Medical Sciences

Research output: Contribution to journal › Article › peer-review

39 Citations (Scopus)

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 language	English
Pages (from-to)	39-42
Number of pages	4
Journal	Human Mutation
Volume	38
Issue number	1
Early online date	21 Sept 2016
DOIs	https://doi.org/10.1002/humu.23116
Publication status	Published - 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.

Keywords

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

Access to Document

10.1002/humu.23116Licence: Unspecified

Cite this

Igarashi, M., Takasawa, K., Hakoda, A., Kanno, J., Takada, S., Miyado, M., Baba, T., Morohashi, K.-I., Tajima, T., Hata, K., Nakabayashi, K., Matsubara, Y., Sekido, R., Ogata, T., Kashimada, K., & 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

Igarashi, M, Takasawa, K, Hakoda, A, Kanno, J, Takada, S, Miyado, M, Baba, T, Morohashi, K-I, Tajima, T, Hata, K, Nakabayashi, K, Matsubara, Y, Sekido, R, Ogata, T, Kashimada, K & Fukami, M 2017, 'Identical NR5A1 Missense Mutations in Two Unrelated 46,XX Individuals with Testicular Tissues', Human Mutation, vol. 38, no. 1, pp. 39-42. https://doi.org/10.1002/humu.23116

@article{73954f074b9b4a418bbc0a5b141545cf,

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

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.",

keywords = "NR0B1, NR5A1, SOX9, 46,XX ovotesticular DSD, 46,XX testicular DSD",

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

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. ",

year = "2017",

month = jan,

day = "1",

doi = "10.1002/humu.23116",

language = "English",

volume = "38",

pages = "39--42",

journal = "Human Mutation",

issn = "1059-7794",

publisher = "Wiley-Liss Inc.",

number = "1",

}

TY - JOUR

T1 - Identical NR5A1 Missense Mutations in Two Unrelated 46,XX Individuals with Testicular Tissues

AU - Igarashi, Maki

AU - Takasawa, Kei

AU - Hakoda, Akiko

AU - Kanno, Junko

AU - Takada, Shuji

AU - Miyado, Mami

AU - Baba, Takashi

AU - Morohashi, Ken-Ichirou

AU - Tajima, Toshihiro

AU - Hata, Kenichiro

AU - Nakabayashi, Kazuhiko

AU - Matsubara, Yoichi

AU - Sekido, Ryohei

AU - Ogata, Tsutomu

AU - Kashimada, Kenichi

AU - Fukami, Maki

N1 - 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.

PY - 2017/1/1

Y1 - 2017/1/1

N2 - 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.

AB - 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.

KW - NR0B1

KW - NR5A1

KW - SOX9

KW - 46,XX ovotesticular DSD

KW - 46,XX testicular DSD

U2 - 10.1002/humu.23116

DO - 10.1002/humu.23116

M3 - Article

C2 - 27610946

SN - 1059-7794

VL - 38

SP - 39

EP - 42

JO - Human Mutation

JF - Human Mutation

IS - 1

ER -

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

Abstract

Bibliographical note

Keywords

Access to Document

Fingerprint

Cite this