RT Journal Article SR Electronic T1 Biallelic variants in MAATS1 encoding CFAP91, a calmodulin-associated and spoke-associated complex protein, cause severe astheno-teratozoospermia and male infertility JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 708 OP 716 DO 10.1136/jmedgenet-2019-106775 VO 57 IS 10 A1 Guillaume Martinez A1 Julie Beurois A1 Denis Dacheux A1 Caroline Cazin A1 Marie Bidart A1 Zine-Eddine Kherraf A1 Derrick R Robinson A1 Véronique Satre A1 Gerald Le Gac A1 Chandran Ka A1 Isabelle Gourlaouen A1 Yann Fichou A1 Graciane Petre A1 Emmanuel Dulioust A1 Raoudha Zouari A1 Nicolas Thierry-Mieg A1 Aminata Touré A1 Christophe Arnoult A1 Mélanie Bonhivers A1 Pierre Ray A1 Charles Coutton YR 2020 UL http://jmg.bmj.com/content/57/10/708.abstract AB Background Multiple morphological abnormalities of the flagella (MMAF) consistently lead to male infertility due to a reduced or absent sperm motility defined as asthenozoospermia. Despite numerous genes recently described to be recurrently associated with MMAF, more than half of the cases analysed remain unresolved, suggesting that many yet uncharacterised gene defects account for this phenotypeMethods Exome sequencing was performed on 167 infertile men with an MMAF phenotype. Immunostaining and transmission electron microscopy (TEM) in sperm cells from affected individuals were performed to characterise the ultrastructural sperm defects. Gene inactivation using RNA interference (RNAi) was subsequently performed in Trypanosoma.Results We identified six unrelated affected patients carrying a homozygous deleterious variants in MAATS1, a gene encoding CFAP91, a calmodulin-associated and spoke-associated complex (CSC) protein. TEM and immunostaining experiments in sperm cells showed severe central pair complex (CPC) and radial spokes defects. Moreover, we confirmed that the WDR66 protein is a physical and functional partner of CFAP91 into the CSC. Study of Trypanosoma MAATS1’s orthologue (TbCFAP91) highlighted high sequence and structural analogies with the human protein and confirmed the axonemal localisation of the protein. Knockdown of TbCFAP91 using RNAi impaired flagellar movement led to CPC defects in Trypanosoma as observed in humans.Conclusions We showed that CFAP91 is essential for normal sperm flagellum structure and function in human and Trypanosoma and that biallelic variants in this gene lead to severe flagellum malformations resulting in astheno-teratozoospermia and primary male infertility.