Biallelic variants in MAATS1 encoding CFAP91, a calmodulin-associated and spoke-associated complex protein, cause severe astheno-teratozoospermia and male infertility

Guillaume Martinez (1, 2) , Julie Beurois (1) , Denis Dacheux (3, 4) , Caroline Cazin (1) , Marie Bidart (1, 5) , Zine-Eddine Kherraf (1, 2) , Derrick Robinson (4, 3) , Véronique Satre (1, 2) , Gerald Le Gac (6, 7, 8, 9, 10) , Chandran Ka (6, 7, 8) , Isabelle Gourlaouen (6, 7, 8) , Yann Fichou (6, 7, 8) , Graciane Petre (11) , Emmanuel Dulioust (12, 13, 14) , Raoudha Zouari (15) , Nicolas Thierry-Mieg (16) , Aminata Touré (17) , Christophe Arnoult (1) , Mélanie Bonhivers (3) , Pierre Ray (1, 2) , Charles Coutton (1, 2)

1 IAB - Institute for Advanced Biosciences / Institut pour l'Avancée des Biosciences (Grenoble)
2 CHU - Centre Hospitalier Universitaire [Grenoble]
3 MFP - Microbiologie Fondamentale et Pathogénicité
4 Bordeaux INP - Institut Polytechnique de Bordeaux
5 IBP - Institut de Biologie et de Pathologie [CHU Grenoble]
6 GGB - Génétique, génomique fonctionnelle et biotechnologies (UMR 1078)
7 EFS Bretagne - Etablissement français du sang [Rennes]
8 IBSAM - Institut Brestois Santé Agro Matière
9 Hôpital Morvan [Brest]
10 CHRU Brest - Centre Hospitalier Régional Universitaire de Brest
11 Brain Tech Lab - BrainTech Laboratory [CHU Grenoble Alpes - Inserm U1205]
12 AP-HP - Hôpital Cochin Broca Hôtel Dieu [Paris]
13 UPD5 - Université Paris Descartes - Paris 5
14 USPC - Université Sorbonne Paris Cité
15 Polyclinique les Jasmins [Tunis]
16 TIMC-IMAG-BCM - Biologie Computationnelle et Mathématique
17 IC UM3 (UMR 8104 / U1016) - Institut Cochin

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 phenotype METHODS: 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.

Keywords: genetics; molecular genetics; reproductive medicine

Domains: Life Sciences [q-bio]

Guillaume Martinez, Julie Beurois, Denis Dacheux, Caroline Cazin, Marie Bidart, et al.. Biallelic variants in MAATS1 encoding CFAP91, a calmodulin-associated and spoke-associated complex protein, cause severe astheno-teratozoospermia and male infertility. Journal of Medical Genetics, 2020, 57 (10), pp.708-716. ⟨10.1136/jmedgenet-2019-106775⟩. ⟨hal-03004959⟩