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

• Published in: American journal of human genetics Vol. 105; no. 6; pp. 1148 - 1167
• Main Authors: Lorès, Patrick, Dacheux, Denis, Kherraf, Zine-Eddine, Nsota Mbango, Jean-Fabrice, Coutton, Charles, Stouvenel, Laurence, Ialy-Radio, Come, Amiri-Yekta, Amir, Whitfield, Marjorie, Schmitt, Alain, Cazin, Caroline, Givelet, Maëlle, Ferreux, Lucile, Fourati Ben Mustapha, Selima, Halouani, Lazhar, Marrakchi, Ouafi, Daneshipour, Abbas, El Khouri, Elma, Do Cruzeiro, Marcio, Favier, Maryline, Guillonneau, François, Chaudhry, Marhaba, Sakheli, Zeinab, Wolf, Jean-Philippe, Patrat, Catherine, Gacon, Gérard, Savinov, Sergey N., Hosseini, Seyedeh Hanieh, Robinson, Derrick R., Zouari, Raoudha, Ziyyat, Ahmed, Arnoult, Christophe, Dulioust, Emmanuel, Bonhivers, Mélanie, Ray, Pierre F., Touré, Aminata
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 05.12.2019; Elsevier (Cell Press); Elsevier
• Subjects: Animals; asthenozoospermia; Asthenozoospermia - etiology; Asthenozoospermia - metabolism; Asthenozoospermia - pathology; Axoneme - genetics; Axoneme - metabolism; Axoneme - pathology; Biochemistry, Molecular Biology; Biophysics; Cell Behavior; Cellular Biology; Evolution, Molecular; Female; Fertilization in Vitro; flagella; Flagella - genetics; Flagella - metabolism; Flagella - pathology; Humans; infertility; Infertility, Male - etiology; Infertility, Male - metabolism; Infertility, Male - pathology; Life Sciences; Male; Mice, Inbred C57BL; Microbiology and Parasitology; Microtubule-Associated Proteins - genetics; MMAF; Molecular biology; mouse; Mutation; Parasitology; Protistology; sperm; Subcellular Processes; TPR; Trypanosoma brucei brucei - physiology; trypanosome; Trypanosomiasis; TTC29; MMAF; flagella; mouse; trypanosome; TPR; asthenozoospermia; sperm; infertility; TTC29
• ISSN: 0002-9297; 1537-6605; 1537-6605
• DOI: 10.1016/j.ajhg.2019.10.007

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.