Mutations in CFAP43 and CFAP44 cause male infertility and flagellum defects in Trypanosoma and human

Nat Commun. 2018 Feb 15;9(1):686. doi: 10.1038/s41467-017-02792-7.

Abstract

Spermatogenesis defects concern millions of men worldwide, yet the vast majority remains undiagnosed. Here we report men with primary infertility due to multiple morphological abnormalities of the sperm flagella with severe disorganization of the sperm axoneme, a microtubule-based structure highly conserved throughout evolution. Whole-exome sequencing was performed on 78 patients allowing the identification of 22 men with bi-allelic mutations in DNAH1 (n = 6), CFAP43 (n = 10), and CFAP44 (n = 6). CRISPR/Cas9 created homozygous CFAP43/44 male mice that were infertile and presented severe flagellar defects confirming the human genetic results. Immunoelectron and stimulated-emission-depletion microscopy performed on CFAP43 and CFAP44 orthologs in Trypanosoma brucei evidenced that both proteins are located between the doublet microtubules 5 and 6 and the paraflagellar rod. Overall, we demonstrate that CFAP43 and CFAP44 have a similar structure with a unique axonemal localization and are necessary to produce functional flagella in species ranging from Trypanosoma to human.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Animals
  • Axoneme
  • Clustered Regularly Interspaced Short Palindromic Repeats
  • Cohort Studies
  • Cytoskeletal Proteins
  • Fertility
  • Flagella / metabolism
  • Flagella / physiology*
  • Homozygote
  • Humans
  • Infertility, Male / genetics*
  • Male
  • Mice
  • Mice, Knockout
  • Microscopy, Immunoelectron
  • Microtubule Proteins / genetics*
  • Middle Aged
  • Mutation*
  • Nuclear Proteins / genetics*
  • Peptide Hydrolases / genetics*
  • Sperm Motility
  • Spermatozoa / metabolism
  • Spermatozoa / physiology*
  • Trypanosoma / physiology*
  • Whole Exome Sequencing

Substances

  • CFAP43 protein, human
  • Cytoskeletal Proteins
  • Microtubule Proteins
  • Nuclear Proteins
  • CFAP44 protein, human
  • Peptide Hydrolases