TEX11 is mutated in infertile men with azoospermia and regulates genome‐wide recombination rates in mouse
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 analog...
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Veröffentlicht in: | EMBO molecular medicine 2015-09, Vol.7 (9), p.1198-1210 |
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Zusammenfassung: | 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.
Graphical 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. |
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ISSN: | 1757-4676 1757-4684 |
DOI: | 10.15252/emmm.201404967 |