Human Male Infertility Associated with Mutations in NR5A1 Encoding Steroidogenic Factor 1

Abstract

One in seven couples worldwide are infertile, and male factor infertility accounts for approximately 30%-50% of these cases. Although many genes are known to be essential for gametogenesis, there are surprisingly few monogenic mutations that have been conclusively demonstrated to cause human spermatogenic failure. A nuclear receptor, NR5A1 (also called steroidogenic factor 1), is a key transcriptional regulator of genes involved in the hypothalamic-pituitary-steroidogenic axis, and it is expressed in the steroidogenic tissue of the developing and adult human gonad. Mutations of NR5A1 have been reported in 46,XY disorders of sex development and in 46,XX primary ovarian insufficiency. To test the hypothesis that mutations in NR5A1 cause male infertility, we sequenced NR5A1 in 315 men with idiopathic spermatogenic failure. We identified seven men with severe spermatogenic failure who carried missense mutations in NR5A1. Functional studies indicated that these mutations impaired NR5A1 transactivational activity. We did not observe these mutations in more than 4000 control alleles, including the entire coding sequence of 359 normospermic men and 370 fertile male controls. NR5A1 mutations are found in approximately 4% of men with otherwise unexplained severe spermatogenic failure.

Wide spectrum of NR5A1‐related phenotypes in 46,XY and 46,XX individuals

“…First, interallelic association with the known p.Gly146Ala polymorphism (rs1110061) may further reduce NR5A1 activity and contribute to more severe phenotypes (WuQiang et al, 2003; Hasegawa et al, 2004; Wada et al, 2006; Reuter et al, 2007; Köhler et al, 2008; Lourenço et al, 2009; Bashamboo et al, 2010a; Paris et al, 2011; Camats et al, 2012). However, two patients in our cohort also bore the p.Gly146Ala variant besides the pathogenic NR5A1 variants, p.Trp302Cys and p.Tyr404*, and their phenotype was not strikingly distinct or more severe.…”

“…Male infertility has been also related to the presence of NR5A1 defects (Bashamboo et al, 2010a; Ferlin et al, 2015). Patients with moderate/severe oligospermia or azoospermia and NR5A1 mutations may have normal testosterone and normal low or low inhibin B levels, but they are at potential risk of deterioration of testicular hormonal secretion with age and may need counseling regarding preservation of sperm and regular monitoring of endocrine function (Bashamboo et al, 2010a).…”

Comprehensive sequence analysis of the NR5A1 gene encoding steroidogenic factor 1 in a large group of infertile males

“…[6][7][8] Although many efforts have been undertaken to identify new causative genes for human male infertility, no candidate gene has been recognised to be administrable in patient care so far. [9][10][11] In contrast, Bashamboo et al 12 found mutations in the NR5A1 gene (MIM 184757) encoding steroidogenic factor 1 (SF1) protein in a substantial fraction of 4% of infertile men (N ¼ 315) with unexplained reduced sperm counts and sperm concentrations below 1 million/ml. All of these were missense mutations leading to reduced protein function in vitro.…”

“…All of these were missense mutations leading to reduced protein function in vitro. 12 The SF1 protein has a central role in gonadal development and steroidogenesis, and both male and female Nr5a1 null mice exhibit adrenal agenesis, have female internal genitalia, and gonadal agenesis. 13 Mutations in NR5A1 were first described in patients with primary adrenal insufficiency and 46,XY disorders of sexual development and recently also in women with primary ovarian insufficiency and boys with hypospadias, bilateral anorchia and/or micropenis broadening the phenotypic spectrum.…”

Association analysis identifies new risk loci for non-obstructive azoospermia in Chinese men

“…A significant proportion of male infertility is accompanied by idiopathic azoospermia, most often presenting as non-obstructive azoospermia (NOA), which occurs in B1% of all adult men 3 . A few studies have reported that genetic factors including chromosome number defects, Y-chromosome microdeletions and autosomal mutations or polymorphisms in multiple biological pathways are involved in the development of NOA [4][5][6] .…”