TEX11 is mutated in infertile men with azoospermia and regulates genome‐wide recombination rates in mouse

Fang Yang, Sherman Silber, N Adrian Leu, Robert D Oates, Janet D Marszalek, Helen Skaletsky, Laura G Brown, Steve Rozen, David C Page, P Jeremy Wang, 01.07.2015

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.

YANG, Fang, et al. TEX11 is mutated in infertile men with azoospermia and regulates genome‐wide recombination rates in mouse. EMBO molecular medicine, 2015, 7. Jg., Nr. 9, S. 1198-1210.

Publication: https://doi.org/10.15252/emmm.201404967

Disclaimer

The publication TEX11 is mutated in infertile men with azoospermia and regulates genome‐wide recombination rates in mouse by Fang Yang, Sherman Silber, N Adrian Leu, Robert D Oates, Janet D Marszalek, Helen Skaletsky, Laura G Brown, Steve Rozen, David C Page, P Jeremy Wang is published under an open access license: https://creativecommons.org/licenses/by/4.0/. Granted rights: share — copy and redistribute the material in any medium or format and adapt — remix, transform, and build upon the material.

Curation by the MFGA team
Relevant data sets presented in the publication have been identified. If possible, annotations (title, general information, conditions, processed tissue types and processed cell types) have been added based on information from the publication. Data tables and images that provide a good overview on the publication's findings on the data set have been extracted from the publication and/or supplement. If not stated otherwise, images are depicted with title and description exactly as in the publication. Tables have been adjusted to the MFGA table format. Conducted adjustments are explained in the detailed view of the tables. However, titles and descriptions have been adopted from the publication.

Data set 1: Frequent singleton TEX11 mutations in men with spermatogenic failure and the identification of missense mutations causing chromosomal synapsis defects

Genome: Other

Species

Species
Human

Conditions

Human phenotype ontology	Participants	Comment
HP:0011961: Non-obstructive azoospermia	246
HP:control	175	men known to have fathered children (n = 93) and men of unknown fertility selected to represent worldwide genetic diversity based on their Y-chromosomal haplotypes (n = 82, samples from the NIH polymorphism discovery panel, Coriell Cell Repositories, and from our collection)

Tissue Types

BRENDA tissue ontology	Maturity	Description	Species	Replicates
BTO_0001363: testis	Adult		Human

Cell Types

Cell ontology	Maturity	Description	Species	Replicates	Cells per replicate
CL_0000017: spermatocyte	Adult	zygotene and pachytene	Human

Images

Figure 1 B: Complex frameshift mutation (patient WHT3759)

The nucleotide sequence in exon 16 (in parentheses) changes from ACT(GATG)CCC to ACT(TTGGTA)CCC, resulting in a net insertion of two bases and generation of a KpnI restriction site (underlined). We confirmed heterozygosity of the mother (WHT4067) by KpnI digestion of PCR products (data not shown).

Source: YANG, Fang, et al. TEX11 is mutated in infertile men with azoospermia and regulates genome‐wide recombination rates in mouse. EMBO molecular medicine, 2015, 7. Jg., Nr. 9, S. 1198-1210.

Licensed under: https://creativecommons.org/licenses/by/4.0/

Figure 1 C: Testicular maturation arrest in the patient (WHT3759)

Testicular tissue obtained by biopsy was sectioned and stained with hematoxylin/eosin. Seminiferous tubules contained meiotic germ cells such as zygotene (ZS, arrowheads) and pachytene spermatocytes (PS, arrows), but no post-meiotic germ cells such as round spermatids were detectable. Scale bar, 25 μm.

Source: YANG, Fang, et al. TEX11 is mutated in infertile men with azoospermia and regulates genome‐wide recombination rates in mouse. EMBO molecular medicine, 2015, 7. Jg., Nr. 9, S. 1198-1210.

Licensed under: https://creativecommons.org/licenses/by/4.0/

Figure 5 A: Schematic representation of missense and nonsense mutations in human

Schematic representation of missense and nonsense mutations in human TEX11 found exclusively in men with azoospermia. The full-length TEX11 protein (GenBank accession number: NP_112566) contains 925 residues. The tetratricopeptide-like (TPR-like) helical domain, found in proteins that form large complexes, extends from residues 161 through 499 (Blatch & Lassle, 1999). Four of the residues mutated in azoospermic men (W117, V142, Q172, and V748) are conserved between human and mouse TEX11 proteins (Supplementary Fig S1).

Source: YANG, Fang, et al. TEX11 is mutated in infertile men with azoospermia and regulates genome‐wide recombination rates in mouse. EMBO molecular medicine, 2015, 7. Jg., Nr. 9, S. 1198-1210.

Licensed under: https://creativecommons.org/licenses/by/4.0/

Results

Data set 2: Experimental transfer of Tex11 from the X chromosome to an autosome