title: 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.
authors.affiliation: Human Developmental Genetics, Institut Pasteur, 75724 Paris, France. anu.bashamboo@pasteur.fr
authors.forename: Anu
authors.initials: A
authors.lastname: Bashamboo
authors.forename: Bruno
authors.initials: B
authors.lastname: Ferraz-de-Souza
authors.forename: Diana
authors.initials: D
authors.lastname: Lourenço
authors.forename: Lin
authors.initials: L
authors.lastname: Lin
authors.forename: Neil J
authors.initials: NJ
authors.lastname: Sebire
authors.forename: Debbie
authors.initials: D
authors.lastname: Montjean
authors.forename: Joelle
authors.initials: J
authors.lastname: Bignon-Topalovic
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Mandelbaum
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Siffroi
authors.forename: Sophie
authors.initials: S
authors.lastname: Christin-Maitre
authors.forename: Uppala
authors.initials: U
authors.lastname: Radhakrishna
authors.forename: Hassan
authors.initials: H
authors.lastname: Rouba
authors.forename: Celia
authors.initials: C
authors.lastname: Ravel
authors.forename: Jacob
authors.initials: J
authors.lastname: Seeler
authors.forename: John C
authors.initials: JC
authors.lastname: Achermann
authors.forename: Ken
authors.initials: K
authors.lastname: McElreavey
mesh_terms: D000595:Amino Acid Sequence; D001483:Base Sequence; D005602:France; D006801:Humans; D007248:Infertility, Male / Q000235:genetics*; D008297:Male; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D020125:Mutation, Missense / Q000235:genetics; D017422:Sequence Analysis, DNA; D013091:Spermatogenesis / Q000235:genetics*; D054339:Steroidogenic Factor 1 / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics*
chemical_list: C515057:NR5A1 protein, human; D054339:Steroidogenic Factor 1