CFAP45 deficiency causes situs abnormalities and asthenospermia by disrupting an axonemal adenine nucleotide homeostasis module

Gerard W Dougherty, Katsutoshi Mizuno, Tabea Nöthe-Menchen, Yayoi Ikawa, Karsten Boldt, Asaf Ta-Shma, Isabella Aprea, Katsura Minegishi, Yuan-Ping Pang, Petra Pennekamp, Niki T Loges, Johanna Raidt, Rim Hjeij, Julia Wallmeier, Huda Mussaffi, Zeev Perles, Orly Elpeleg, Franziska Rabert, Hidetaka Shiratori, Stef J LetteboerNicola Horn, Samuel Young, Timo Strünker, Friederike Stumme, Claudius Werner, Heike Olbrich, Katsuyoshi Takaoka, Takahiro Ide, Wang Kyaw Twan, Luisa Biebach, Jörg Große-Onnebrink, Judith A Klinkenbusch, Kavita Praveen, Diana C Bracht, Inga M Höben, Katrin Junger, Jana Gützlaff, Sandra Cindrić, Micha Aviram, Thomas Kaiser, Yasin Memari, Petras P Dzeja, Bernd Dworniczak, Marius Ueffing, Ronald Roepman, Kerstin Bartscherer, Nicholas Katsanis, Erica E Davis, Israel Amirav, Hiroshi Hamada, Heymut Omran

Research output: Contribution to journal/periodicalArticleScientificpeer-review

Abstract

Axonemal dynein ATPases direct ciliary and flagellar beating via adenosine triphosphate (ATP) hydrolysis. The modulatory effect of adenosine monophosphate (AMP) and adenosine diphosphate (ADP) on flagellar beating is not fully understood. Here, we describe a deficiency of cilia and flagella associated protein 45 (CFAP45) in humans and mice that presents a motile ciliopathy featuring situs inversus totalis and asthenospermia. CFAP45-deficient cilia and flagella show normal morphology and axonemal ultrastructure. Proteomic profiling links CFAP45 to an axonemal module including dynein ATPases and adenylate kinase as well as CFAP52, whose mutations cause a similar ciliopathy. CFAP45 binds AMP in vitro, consistent with structural modelling that identifies an AMP-binding interface between CFAP45 and AK8. Microtubule sliding of dyskinetic sperm from Cfap45-/- mice is rescued with the addition of either AMP or ADP with ATP, compared to ATP alone. We propose that CFAP45 supports mammalian ciliary and flagellar beating via an adenine nucleotide homeostasis module.

Original languageEnglish
Pages (from-to)5520
JournalNature Communications
Volume11
Issue number1
DOIs
Publication statusPublished - 02 Nov 2020

Keywords

  • Adenine Nucleotides/metabolism
  • Adolescent
  • Adult
  • Animals
  • Asthenozoospermia/genetics
  • Axoneme/ultrastructure
  • CRISPR-Cas Systems/genetics
  • Cilia/metabolism
  • Cytoskeletal Proteins/deficiency
  • DNA Mutational Analysis
  • Disease Models, Animal
  • Epididymis/pathology
  • Female
  • Flagella/metabolism
  • Humans
  • Loss of Function Mutation
  • Male
  • Mice
  • Mice, Knockout
  • Middle Aged
  • Planarians/cytology
  • Respiratory Mucosa/cytology
  • Situs Inversus/diagnostic imaging
  • Sperm Motility/genetics
  • Tomography, X-Ray Computed
  • Whole Exome Sequencing

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