eLife (Nov 2023)

Novel axonemal protein ZMYND12 interacts with TTC29 and DNAH1, and is required for male fertility and flagellum function

  • Denis Dacheux,
  • Guillaume Martinez,
  • Christine E Broster Reix,
  • Julie Beurois,
  • Patrick Lores,
  • Magamba Tounkara,
  • Jean-William Dupuy,
  • Derrick Roy Robinson,
  • Corinne Loeuillet,
  • Emeline Lambert,
  • Zeina Wehbe,
  • Jessica Escoffier,
  • Amir Amiri-Yekta,
  • Abbas Daneshipour,
  • Seyedeh-Hanieh Hosseini,
  • Raoudha Zouari,
  • Selima Fourati Ben Mustapha,
  • Lazhar Halouani,
  • Xiaohui Jiang,
  • Ying Shen,
  • Chunyu Liu,
  • Nicolas Thierry-Mieg,
  • Amandine Septier,
  • Marie Bidart,
  • Véronique Satre,
  • Caroline Cazin,
  • Zine Eddine Kherraf,
  • Christophe Arnoult,
  • Pierre F Ray,
  • Aminata Toure,
  • Mélanie Bonhivers,
  • Charles Coutton

DOI
https://doi.org/10.7554/eLife.87698
Journal volume & issue
Vol. 12

Abstract

Read online

Male infertility is common and complex, presenting a wide range of heterogeneous phenotypes. Although about 50% of cases are estimated to have a genetic component, the underlying cause often remains undetermined. Here, from whole-exome sequencing on samples from 168 infertile men with asthenoteratozoospermia due to severe sperm flagellum, we identified homozygous ZMYND12 variants in four unrelated patients. In sperm cells from these individuals, immunofluorescence revealed altered localization of DNAH1, DNALI1, WDR66, and TTC29. Axonemal localization of ZMYND12 ortholog TbTAX-1 was confirmed using the Trypanosoma brucei model. RNAi knock-down of TbTAX-1 dramatically affected flagellar motility, with a phenotype similar to the sperm from men bearing homozygous ZMYND12 variants. Co-immunoprecipitation and ultrastructure expansion microscopy in T. brucei revealed TbTAX-1 to form a complex with TTC29. Comparative proteomics with samples from Trypanosoma and Ttc29 KO mice identified a third member of this complex: DNAH1. The data presented revealed that ZMYND12 is part of the same axonemal complex as TTC29 and DNAH1, which is critical for flagellum function and assembly in humans, and Trypanosoma. ZMYND12 is thus a new asthenoteratozoospermia-associated gene, bi-allelic variants of which cause severe flagellum malformations and primary male infertility.

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