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 - Funding Information:
This study was supported by the National Center Biobank Network, the Grants-in-Aid from the Japan Society for the Promotion of Science (26293224); the Grant-in-Aid for Scientific Research on Innovative Areas from the Ministry of Education, Culture, Sports, Science and Technology; and grants from the Ministry of Health, Labor and Welfare, the Japan Agency for Medical Research and Development, the National Center for Child Health and Development (26-11), and the Takeda foundation. We thank Dr. Robin Lovell-Badge at the Francis Crick Institute for providing us the TESCO reporter vector.
Publisher Copyright:
© 2016 WILEY PERIODICALS, INC.
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 - 46,XX ovotesticular DSD
KW - 46,XX testicular DSD
KW - NR0B1
KW - NR5A1
KW - SOX9
UR - http://www.scopus.com/inward/record.url?scp=85003706947&partnerID=8YFLogxK
UR - https://abdn.pure.elsevier.com/en/publications/identical-nr5a1-missense-mutations-in-two-unrelated-46xx-individu
U2 - 10.1002/humu.23116
DO - 10.1002/humu.23116
M3 - Article
C2 - 27610946
AN - SCOPUS:85003706947
SN - 1059-7794
VL - 38
SP - 39
EP - 42
JO - Human Mutation
JF - Human Mutation
IS - 1
ER -