Human male infertility associated with mutations in NR5A1 encoding steroidogenic factor 1.
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.
Bashamboo
Anu
A
Human Developmental Genetics, Institut Pasteur, 75724 Paris, France. anu.bashamboo@pasteur.fr
Ferraz-de-Souza
Bruno
B
Lourenço
Diana
D
Lin
Lin
L
Sebire
Neil J
NJ
Montjean
Debbie
D
Bignon-Topalovic
Joelle
J
Mandelbaum
Jacqueline
J
Siffroi
Jean-Pierre
JP
Christin-Maitre
Sophie
S
Radhakrishna
Uppala
U
Rouba
Hassan
H
Ravel
Celia
C
Seeler
Jacob
J
Achermann
John C
JC
McElreavey
Ken
K
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*
C515057:NR5A1 protein, human; D054339:Steroidogenic Factor 1