2. Academic Validation
  3. Mutations in TTC29, Encoding an Evolutionarily Conserved Axonemal Protein, Result in Asthenozoospermia and Male Infertility

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

  • Am J Hum Genet. 2019 Dec 5;105(6):1148-1167. doi: 10.1016/j.ajhg.2019.10.007.
Patrick Lorès 1,  Denis Dacheux 2,  Zine-Eddine Kherraf 3,  Jean-Fabrice Nsota Mbango 1,  Charles Coutton 4,  Laurence Stouvenel 1,  Come Ialy-Radio 1,  Amir Amiri-Yekta 5,  Marjorie Whitfield 1,  Alain Schmitt 1,  Caroline Cazin 6,  Maëlle Givelet 1,  Lucile Ferreux 7,  Selima Fourati Ben Mustapha 8,  Lazhar Halouani 8,  Ouafi Marrakchi 8,  Abbas Daneshipour 5,  Elma El Khouri 1,  Marcio Do Cruzeiro 1,  Maryline Favier 1,  François Guillonneau 1,  Marhaba Chaudhry 1,  Zeinab Sakheli 1,  Jean-Philippe Wolf 9,  Catherine Patrat 9,  Gérard Gacon 1,  Sergey N Savinov 10,  Seyedeh Hanieh Hosseini 11,  Derrick R Robinson 12,  Raoudha Zouari 8,  Ahmed Ziyyat 13,  Christophe Arnoult 6,  Emmanuel Dulioust 9,  Mélanie Bonhivers 12,  Pierre F Ray 3,  Aminata Touré 14
Affiliations

Affiliations

  • 1 INSERM U1016, Institut Cochin, Paris 75014, France; Centre National de la Recherche Scientifique UMR8104, Paris 75014, France; Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris 75014, France.
  • 2 Université de Bordeaux, Microbiologie Fondamentale et Pathogénicité, CNRS UMR 5234, Bordeaux, France; Institut Polytechnique de Bordeaux, Microbiologie Fondamentale et Pathogénicité, UMR-CNRS 5234, 33000 Bordeaux, France.
  • 3 INSERM U1209, CNRS UMR 5309, Université Grenoble Alpes, 38000 Grenoble, France; CHU de Grenoble, UM GI-DPI, Grenoble 38000, France.
  • 4 INSERM U1209, CNRS UMR 5309, Université Grenoble Alpes, 38000 Grenoble, France; CHU Grenoble Alpes, UM de Génétique Chromosomique, Grenoble, France.
  • 5 Department of Genetics, Reproductive Biomedicine Research Center, Royan Institute for Reproductive Biomedicine, ACECR, Tehran, Iran.
  • 6 INSERM U1209, CNRS UMR 5309, Université Grenoble Alpes, 38000 Grenoble, France.
  • 7 Laboratoire d'Histologie Embryologie - Biologie de la Reproduction - CECOS Groupe Hospitalier Universitaire Paris Centre, Assistance Publique-Hôpitaux de Paris, Paris 75014, France.
  • 8 Histologie Embryologie et Biologie de la Reproduction, Centre de Promotion des Sciences de la Reproduction, Polyclinique les Jasmins, Centre Urbain Nord, 1003 Tunis, Tunisia.
  • 9 INSERM U1016, Institut Cochin, Paris 75014, France; Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris 75014, France; Laboratoire d'Histologie Embryologie - Biologie de la Reproduction - CECOS Groupe Hospitalier Universitaire Paris Centre, Assistance Publique-Hôpitaux de Paris, Paris 75014, France.
  • 10 Department of Biochemistry and Molecular Biology, University of Massachusetts, Amherst, MA 01003, USA.
  • 11 Department of Andrology, Reproductive Biomedicine Research Center, Royan Institutefor Reproductive Biomedicine, ACECR, Tehran, Iran.
  • 12 Université de Bordeaux, Microbiologie Fondamentale et Pathogénicité, CNRS UMR 5234, Bordeaux, France.
  • 13 INSERM U1016, Institut Cochin, Paris 75014, France; Centre National de la Recherche Scientifique UMR8104, Paris 75014, France; Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris 75014, France; Laboratoire d'Histologie Embryologie - Biologie de la Reproduction - CECOS Groupe Hospitalier Universitaire Paris Centre, Assistance Publique-Hôpitaux de Paris, Paris 75014, France.
  • 14 INSERM U1016, Institut Cochin, Paris 75014, France; Centre National de la Recherche Scientifique UMR8104, Paris 75014, France; Faculté de Médecine, Université Paris Descartes, Sorbonne Paris Cité, Paris 75014, France. Electronic address: aminata.toure@inserm.fr.
PMID: 31735292 DOI: 10.1016/j.ajhg.2019.10.007
Abstract

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.

Keywords

MMAF; TPR; TTC29; asthenozoospermia; flagella; infertility; mouse; sperm; trypanosome.

Figures