TEX11 is mutated in infertile men with azoospermia and regulates genome‐wide recombination rates in mouse. Issue 9 (1st July 2015)

• Record Type: Journal Article
• Authors: Yang, Fang; Silber, Sherman; Leu, N Adrian; Oates, Robert D; Marszalek, Janet D; Skaletsky, Helen; Brown, Laura G; Rozen, Steve; Page, David C; Wang, P Jeremy
• Is Part Of: EMBO molecular medicine. Volume 7:Issue 9(2015:Sep.)
• Page Start: 1198
• Page End: 1210
• Publication Date: 2015-07-01
• Subjects: chromosomal synapsis -- infertility -- meiosis -- recombination -- X chromosome; Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.15252/emmm.201404967
• Languages: English
• ISSNs: 1757-4676

Abstract

Abstract: Genome‐wide recombination is essential for genome stability, evolution, and speciation. Mouse Tex11, an X‐linked meiosis‐specific gene, promotes meiotic recombination and chromosomal synapsis. Here, we report that TEX11 is mutated in infertile men with non‐obstructive azoospermia and that an analogous mutation in the mouse impairs meiosis. Genetic screening of a large cohort of idiopathic infertile men reveals that TEX11 mutations, including frameshift and splicing acceptor site mutations, cause infertility in 1% of azoospermic men. Functional evaluation of three analogous human TEX11 missense mutations in transgenic mouse models identified one mutation (V748A) as a potential infertility allele and found two mutations non‐causative. In the mouse model, an intronless autosomal Tex11 transgene functionally substitutes for the X‐linked Tex11 gene, providing genetic evidence for the X‐to‐autosomal retrotransposition evolution phenomenon. Furthermore, we find that TEX11 protein levels modulate genome‐wide recombination rates in both sexes. These studies indicate that TEX11 alleles affecting expression level or substituting single amino acids may contribute to variations in recombination rates between sexes and among individuals in humans. Synopsis: Mutations were identified in the X chromosome‐linked germ cell‐specific gene TEX11 in infertile men with non‐obstructive azoospermia. Functional studies of TEX11 protein in mice revealed an unexpected role in the regulation of genome‐wide recombination rates. Sequencing screening of human infertile patients reveals mutations in the TEX11 gene in 1% of non‐obstructive azoospermic men. Infertile men with mutations in TEX11 exhibit meiotic arrest. Experimentally retrotransposed Tex11 on an autosome rescues the fertility of male mice deleted for the X‐linked Tex11 gene. Genetic studies of mice with different Tex11 gene dosages demonstrate a threshold level of TEX11 protein for spermatogenesis. Analysis of crossover formation shows that TEX11 regulates genome‐wide recombination rates in both males and females in a dosage‐dependent manner. Abstract : Mutations were identified in the X chromosome‐linked germ cell‐specific gene TEX11 in infertile men with non‐obstructive azoospermia. Functional studies of TEX11 protein in mice revealed an unexpected role in the regulation of genome‐wide recombination rates.