Identical NR5A1 Missense Mutations in Two Unrelated 46,XX Individuals with Testicular Tissues.
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.
Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
Maki
M
Igarashi
Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
Kei
K
Takasawa
Department of Endocrinology, Miyagi Children's Hospital, Sendai, Japan.
Akiko
A
Hakoda
Department of Endocrinology, Miyagi Children's Hospital, Sendai, Japan.
Junko
J
Kanno
Department of Systems BioMedicine, National Research Institute for Child Health and Development, Tokyo, Japan.
Shuji
S
Takada
Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
Mami
M
Miyado
Department of Molecular Biology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Takashi
T
Baba
Department of Molecular Biology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Ken-Ichirou
KI
Morohashi
Department of Pediatrics, Hokkaido University School of Medicine, Sapporo, Japan.
Toshihiro
T
Tajima
Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan.
Kenichiro
K
Hata
Department of Maternal-Fetal Biology, National Research Institute for Child Health and Development, Tokyo, Japan.
Kazuhiko
K
Nakabayashi
National Research Institute for Child Health and Development, Tokyo, Japan.
Yoichi
Y
Matsubara
Institute of Medical Sciences, University of Aberdeen, Aberdeen, United Kingdom.
Ryohei
R
Sekido
Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.|Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, Japan.
Tsutomu
T
Ogata
Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University (TMDU), Tokyo, Japan.
Kenichi
K
Kashimada
Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, Japan.
Maki
M
Fukami
D000483:Alleles; D019943:Amino Acid Substitution; D015415:Biomarkers; D004252:DNA Mutational Analysis; D012734:Disorders of Sex Development / Q000175:diagnosis* / Q000235:genetics*; D005260:Female; D005838:Genotype; D006066:Gonads / Q000002:abnormalities; D006801:Humans; D007223:Infant; D059785:Karyotype; D008297:Male; D008958:Models, Molecular; D020125:Mutation, Missense; D010641:Phenotype; D011487:Protein Conformation; D054339:Steroidogenic Factor 1 / Q000737:chemistry / Q000235:genetics*; D013737:Testis / Q000378:metabolism*
D015415:Biomarkers; D054339:Steroidogenic Factor 1
46,XX ovotesticular DSD; 46,XX testicular DSD; NR0B1; NR5A1; SOX9