RT Journal Article SR Electronic T1 Absence of SCAPER causes male infertility in humans and Drosophila by modulating microtubule dynamics during meiosis JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 254 OP 263 DO 10.1136/jmedgenet-2020-106946 VO 58 IS 4 A1 Ohad Wormser A1 Ygal Levy A1 Anna Bakhrat A1 Silvia Bonaccorsi A1 Lucia Graziadio A1 Maurizio Gatti A1 Ali AbuMadighem A1 Richard J McKenney A1 Kyoko Okada A1 Saad El Riati A1 Iris Har-Vardi A1 Mahmoud Huleihel A1 Eliahu Levitas A1 Ohad S Birk A1 Uri Abdu YR 2021 UL http://jmg.bmj.com/content/58/4/254.abstract AB Background Mutation in S-phase cyclin A-associated protein rin the endoplasmic reticulum (SCAPER) 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 short spindle 3 (ssp3) (SCAPER orthologue) Drosophila CAS9-knockout lines. In vitro microtubule (MT) binding assayed by total internal reflection fluorescence microscopy.Results We show that patients homozygous for a SCAPER 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, Drosophila null mutants for the ubiquitously expressed ssp3 gene are viable and female fertile but male sterile. We further show that male sterility in ssp3 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 SCAPER null mutations block the entry into meiosis of SPG, causing azoospermia. Null mutations in ssp3 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 Drosophila meiosis.