The p.R92W variant ofNR5A1/Nr5a1induces testicular development of 46,XX gonads in humans, but not in mice: phenotypic comparison of human patients and mutation-induced mice.
NR5A1 is the key regulator of adrenal and gonadal development in both humans and mice. Recently, a missense substitution in humanNR5A1, p.R92W, was shown to underlie gonadal dysgenesis in genetic males and testicular formation in genetic females. Here, we investigated the phenotypic effects of the p.R92W mutation on murine development. Mice carrying the p.R92W mutation manifested a similar but milder phenotype than that of the previously describedNr5a1knockout mice. Importantly, mutation-positive XX mice showed no signs of masculinization. These results, together with prior observations, indicate that the p.R92W mutation inNR5A1/Nr5a1encodes unique molecules that disrupt male gonadal development in both humans and mice and induces testicular formation specifically in human females. Our findings provide novel insights into the conservation and divergence in the molecular networks underlying mammalian sexual development.
Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, 157-8535 Japan.
Mami
M
Miyado
Department of Systems BioMedicine, National Research Institute for Child Health and Development, Tokyo, 157-8535 Japan.
Masafumi
M
Inui
Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, 157-8535 Japan.
Maki
M
Igarashi
Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, 157-8535 Japan.
Yuko
Y
Katoh-Fukui
Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University (TMDU), Tokyo, 113-8510 Japan.
Kei
K
Takasawa
Department of Endocrinology, Miyagi Children's Hospital, Sendai, 989-3126 Japan.
Akiko
A
Hakoda
Department of Endocrinology, Miyagi Children's Hospital, Sendai, 989-3126 Japan.
Junko
J
Kanno
Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University (TMDU), Tokyo, 113-8510 Japan.
Kenichi
K
Kashimada
Department of Reproductive Biology, National Research Institute for Child Health and Development, Tokyo, 157-8535 Japan.
Kenji
K
Miyado
Department of Systems BioMedicine, National Research Institute for Child Health and Development, Tokyo, 157-8535 Japan.
Moe
M
Tamano
Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, 157-8535 Japan ; Department of Pediatrics, Hamamatsu University School of Medicine, Hamamatsu, 431-3192 Japan.
Tsutomu
T
Ogata
Department of Systems BioMedicine, National Research Institute for Child Health and Development, Tokyo, 157-8535 Japan.
Shuji
S
Takada
Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo, 157-8535 Japan.
Maki
M
Fukami
Disorders of sex development; Genome editing; Gonadal development; Gonadal dysgenesis; Mouse model; Mutation; SF-1; Sex differentiation