Mutations in TTC29, Encoding an Evolutionarily Conserved Axonemal Protein, Result in Asthenozoospermia and Male Infertility

Lorès, Patrick and Dacheux, Denis and Kherraf, Zine-Eddine and Nsota Mbango, Jean-Fabrice and Coutton, Charles and Stouvenel, Laurence and Ialy-Radio, Come and Amiri-Yekta, Amir and Whitfield, Marjorie and Schmitt, Alain and Cazin, Caroline and Givelet, Maëlle and Ferreux, Lucile and Fourati Ben Mustapha, Selima and Halouani, Lazhar and Marrakchi, Ouafi and Daneshipour, Abbas and El Khouri, Elma and Do Cruzeiro, Marcio and Favier, Maryline and Guillonneau, François and Chaudhry, Marhaba and Sakheli, Zeinab and Wolf, Jean-Philippe and Patrat, Catherine and Gacon, Gérard and Savinov, Sergey N and Hosseini, Seyedeh Hanieh and Robinson, Derrick R and Zouari, Raoudha and Ziyyat, Ahmed and Arnoult, Christophe and Dulioust, Emmanuel and Bonhivers, Mélanie and Ray, Pierre F and Touré, Aminata


In humans, structural or functional defects of the sperm flagellum induce asthenozoospermia, which accounts for the main sperm defect encountered in infertile men. Herein we focused on morphological abnormalities of the sperm flagellum (MMAF), a phenotype also termed “short tails,” which constitutes one of the most severe sperm morphological defects resulting in asthenozoospermia. In previous work based on whole-exome sequencing of a cohort of 167 MMAF-affected individuals, we identified bi-allelic loss-of-function mutations in more than 30% of the tested subjects. In this study, we further analyzed this cohort and identified five individuals with homozygous truncating variants in TTC29, a gene preferentially and highly expressed in the testis, and encoding a tetratricopeptide repeat-containing protein related to the intraflagellar transport (IFT). One individual carried a frameshift variant, another one carried a homozygous stop-gain variant, and three carried the same splicing variant affecting a consensus donor site. The deleterious effect of this last variant was confirmed on the corresponding transcript and protein product. In addition, we produced and analyzed TTC29 loss-of-function models in the flagellated protist T. brucei and in M. musculus. Both models confirmed the importance of TTC29 for flagellar beating. We showed that in T. brucei the TPR structural motifs, highly conserved between the studied orthologs, are critical for TTC29 axonemal localization and flagellar beating. Overall our work demonstrates that TTC29 is a conserved axonemal protein required for flagellar structure and beating and that TTC29 mutations are a cause of male sterility due to MMAF.