Absence of SCAPER causes male infertility in humans and by modulating microtubule dynamics during meiosis.

Background: Mutation () have been found across ethnicities and have been shown to cause variable penetrance of an array of pathological traits, including intellectual disability, retinitis pigmentosa and ciliopathies.

Methods: Human clinical phenotyping, surgical testicular sperm extraction and testicular tissue staining. Generation and analysis of () ( orthologue) CAS9-knockout lines. In vitro microtubule (MT) binding assayed by total internal reflection fluorescence microscopy.

Results: We show that patients homozygous for a mutation lack SCAPER expression in spermatogonia (SPG) and are azoospermic due to early defects in spermatogenesis, leading to the complete absence of meiotic cells Interestingly, a null mutants for the ubiquitously expressed gene are viable and female fertile but male sterile. We further show that male sterility in null mutants is due to failure in both chromosome segregation and cytokinesis. In cells undergoing male meiosis, the MTs emanating from the centrosomes do not appear to interact properly with the chromosomes, which remain dispersed within dividing spermatocytes (SPCs). In addition, mutant SPCs are unable to assemble a normal central spindle and undergo cytokinesis. Consistent with these results, an in vitro assay demonstrated that both SCAPER and Ssp3 directly bind MTs.

Conclusions: Our results show that null mutations block the entry into meiosis of SPG, causing azoospermia. Null mutations in specifically disrupt MT dynamics during male meiosis, leading to sterility. Moreover, both SCAPER and Ssp3 bind MTs in vitro. These results raise the intriguing possibility of a common feature between human and meiosis.