Tex11 Mutant Mouse Models of Human Azoospermia

Abstract

Non-obstructive azoospermia (NOA) is the absence of sperm in the ejaculate due to spermatogenic failure. Fifty percent of NOA cases are unexplained but may arise from unidentified genetic mutations. Variants in TEX11 have been identified in men with NOA; and Tex11 knockout in mice causes NOA. Here we attempt to validate three TEX11 variants discovered in NOA patients by knocking them into the orthologous region of the mouse genome using CRISPR/Cas9 gene editing. Compared to wild type (144.2 {+/-} 9.87 mg; 1.7 {+/-} 0.5 million sperm/cauda epididymis 4.8 {+/-} 1.3 pups/breeding), Tex11D mice (frameshift mutation) had reduced testis weight (28.33 {+/-} 1.16 mg); no sperm in the epididymis; and were infertile with a maturation arrest testicular phenotype. We did not observe any spermatogenesis or fertility defects Tex11A mice (missense mutation). Tex11L mice had reduced testis weight (87.5 {+/-} 14.79 mg) and epididymal sperm counts (0.33{+/-}0.13 million/cauda epididymis) but an incompletely penetrant infertility phenotype (5.4 {+/-} 1.13 pups/breeding) with one third of mice being infertile. Infertile Tex11L mice also had a distinct epididymal phenotype with reduced sperm density in the caput and no sperm in the cauda, which was filled with amorphous material.