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

Abstract

The steroidogenic factor 1 (SF1) protein, encoded by the NR5A1 gene, plays a central role in gonadal development and steroidogenesis. Mutations in NR5A1 were first described in patients with primary adrenal insufficiency and 46,XY disorders of sexual development and later also in men with hypospadias, bilateral anorchia and micropenis and women with primary ovarian insufficiency. Recently, heterozygous missense mutations were found in 4% of infertile men with unexplained reduced sperm counts living in France, but all mutation carriers were of non-Caucasian ancestry. Therefore, we performed a comprehensive NR5A1 sequence analysis in 488 well-characterised predominantly Caucasian patients with azoo-or severe oligozoospermia. Two-hundred-thirty-seven men with normal semen parameters were sequenced as controls. In addition to several synonymous variants of unclear pathogenicity, three heterozygous missense mutations predicted to be damaging to SF1 protein function were identified. The andrological phenotype in infertile but otherwise healthy mutation carriers seems variable. In conclusion, mutations altering SF1 protein function and causing spermatogenic failure are also found in men of German origin, but the prevalence seems markedly lower than in other populations.

Analysis of the gene coding for steroidogenic factor 1 (SF1, NR5A1) in a cohort of 50 Egyptian patients with 46,XY disorders of sex development

“…So far, almost only nonsense mutations in the hinge region have been reported in the DSD phenotypes (9,10,16,17,21,30,34), hypospadias (8,9), 46,XX primary ovarian insufficiency (16,17) and premature ovarian failure (9). In contrast, only missense mutations in the hinge region were detected in the minor DSD phenotype of male infertility (13,14) (Table 2).…”

“…So far, there is no apparent genotype-phenotype correlation in patients with NR5A1 mutations. The phenotypic spectrum has been extended, involving not only ambiguous genitalia and hypospadias due to gonadal dysgenesis (8,9,10), but also vanishing testis syndrome (11), isolated hypoplastic penis (12) and male infertility (13,14). Moreover, NR5A1 mutations were also found in 46,XX females with premature ovarian failure and primary ovarian insufficiency (15,16,17,18,19).…”

“…As the clinical consequences are not yet clear, more outcome data are needed before recommending general screening of NR5A1 in isolated hypospadias. However, future mild progressive effects on the gonadals resulting in male infertility cannot be excluded in this case, as also infertile males with normal male phenotypes and NR5A1 mutations were described recently (13,14).…”

The signaling phospholipid PIP 3 creates a new interaction surface on the nuclear receptor SF-1

“…2C). Loss-offunction heterozygous human NR5A1 mutations R255L, R255C, and D257N present in L2-3 are associated with human diseases, including adrenal insufficiency (17), premature ovarian failure (18), and male infertility (19). The SF-1/PIP 3 structure reveals that both of these conserved residues, R255 and D257, interact with each other and form an anchoring cluster that organizes the proteinlipid surface at the entrance of the hormone pocket (Fig.…”

“…Indeed, in published ligand-bound SF-1 structures, critical surface loops in the vicinity of the pocket entrance remain poorly ordered. This region is functionally important because it harbors diseaseassociated mutations in SF-1 (17)(18)(19). We hypothesized that phosphoinositide ligands with their charged head groups might anchor this site to render SF-1 fully functional.…”