A novel mouse allele of the DNA/RNA helicase senataxin ( Setx spcar3 ) causing meiotic arrest of spermatocytes and male infertility

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An unbiased screen for discovering novel genes for fertility identified the spcar3, spermatocyte arrest 3, mutant phenotype. The spcar3 mutation identified a new allele of the Setx gene, encoding senataxin, a DNA/RNA helicase that regulates transcription termination by resolving DNA/RNA hybrid R-loop structures. Although mutations in the human SETX gene cause neural disorders, Setx spcar3 mutant mice do not show any apparent neural phenotype, but instead exhibit male infertility and female subfertility. Histology of the Setx spcar3 mutant testes revealed absence of spermatids and mature spermatozoa in the seminiferous tubules. Cytological analysis of chromosome spread preparations of the Setx spcar3 mutant spermatocytes revealed normal synapsis, but aberrant DNA damage in the autosomes, and defective formation of the sex body. Furthermore, Setx spcar3 testicular cells exhibited abnormal accumulation of R-loops compared to wild type testicular cells. Transient expression assays identified regions of the senataxin protein required for sub-nuclear localization. Together, these results not only confirm that senataxin is required for normal meiosis and spermatogenesis but also provide a new resource for determination of its role in maintaining R-loop formation and genome integrity.

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