The p.R92W variant of NR5A1/Nr5a1 induces testicular development of 46,XX gonads in humans, but not in mice: phenotypic comparison of human patients and mutation-induced mice.

Masafumi Inui,Yuko Katoh-Fukui,Kenichi Kashimada,Tsutomu Ogata,Junko Kanno,Kenji Miyado,Mami Miyado,Moe Tamano,Kei Takasawa,Shuji Takada,Akiko Hakoda,Maki Fukami,Maki Igarashi

doi:10.1186/s13293-016-0114-6

Abstract

NR5A1 is the key regulator of adrenal and gonadal development in both humans and mice. Recently, a missense substitution in human NR5A1, 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 described Nr5a1 knockout mice. Importantly, mutation-positive XX mice showed no signs of masculinization. These results, together with prior observations, indicate that the p.R92W mutation in NR5A1/Nr5a1 encodes 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.

Highlights

Nuclear receptor subfamily 5 group A member 1 (NR5A1) plays a critical role in the development of the adrenal gland and gonad in human [1, 2]
* Correspondence: fukami-m@ncchd.go.jp 1Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan Full list of author information is available at the end of the article patients with 46,XX testicular/ovotesticular disorders of sex development (DSD) [4]. This mutation affects a highly conserved amino acid in the DNA binding domain of the wild-type (WT) NR5A1 protein. These findings provide the first indication that specific NR5A1 mutations can switch the developmental processes of immature 46,XX gonads toward testicular formation
Histological analyses revealed that while the testicular cords were recognizable in the gonads of WT XY mice at 13.5 and 18.5 dpc, such structures were not apparent in the gonads of Nr5a1p.R92W/p.R92W XY mice at both stages (Fig. 2)

Summary

Introduction

Nuclear receptor subfamily 5 group A member 1 (NR5A1) plays a critical role in the development of the adrenal gland and gonad in human [1, 2]. Heterozygous loss-of-function mutations in NR5A1 account for a certain percentage of the etiology of gonadal dysgenesis in 46,XY individuals and a small fraction of the genetic causes of ovarian insufficiency in 46,XX individuals [1,2,3]. NR5A1 mutations rarely underlie adrenal insufficiency, indicating that during human development, gonads are more vulnerable than adrenal glands to the reduced NR5A1 activity [1, 2]. Murine NR5A1 has 94 % amino acid homology with human NR5A1 and is involved in adrenal and gonadal development [1, 2, 7, 8].

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Conclusion