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. Letteboer, Nicola 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 and Heymut Omran ()
Additional contact information
Gerard W. Dougherty: University Hospital Münster
Katsutoshi Mizuno: RIKEN Center for Biosystems Dynamics Research
Tabea Nöthe-Menchen: University Hospital Münster
Yayoi Ikawa: RIKEN Center for Biosystems Dynamics Research
Karsten Boldt: University of Tübingen
Asaf Ta-Shma: Hadassah-Hebrew University Medical Center
Isabella Aprea: University Hospital Münster
Katsura Minegishi: RIKEN Center for Biosystems Dynamics Research
Yuan-Ping Pang: Mayo Clinic
Petra Pennekamp: University Hospital Münster
Niki T. Loges: University Hospital Münster
Johanna Raidt: University Hospital Münster
Rim Hjeij: University Hospital Münster
Julia Wallmeier: University Hospital Münster
Huda Mussaffi: Schneider Children’s Medical Center
Zeev Perles: Hadassah-Hebrew University Medical Center
Orly Elpeleg: Hadassah-Hebrew University Medical Center
Franziska Rabert: Max Planck Institute for Molecular Biomedicine
Hidetaka Shiratori: Osaka University
Stef J. Letteboer: Radboud University Medical Center
Nicola Horn: University of Tübingen
Samuel Young: University of Münster
Timo Strünker: University of Münster
Friederike Stumme: University Hospital Münster
Claudius Werner: University Hospital Münster
Heike Olbrich: University Hospital Münster
Katsuyoshi Takaoka: RIKEN Center for Biosystems Dynamics Research
Takahiro Ide: RIKEN Center for Biosystems Dynamics Research
Wang Kyaw Twan: RIKEN Center for Biosystems Dynamics Research
Luisa Biebach: University Hospital Münster
Jörg Große-Onnebrink: University Hospital Münster
Judith A. Klinkenbusch: University Hospital Münster
Kavita Praveen: Duke University Medical Center
Diana C. Bracht: University Hospital Münster
Inga M. Höben: University Hospital Münster
Katrin Junger: University of Tübingen
Jana Gützlaff: University Hospital Münster
Sandra Cindrić: University Hospital Münster
Micha Aviram: Soroka Medical Center
Thomas Kaiser: University Hospital Münster
Yasin Memari: Addenbrooke’s Hospital
Petras P. Dzeja: Mayo Clinic
Bernd Dworniczak: University of Münster
Marius Ueffing: University of Tübingen
Ronald Roepman: Radboud University Medical Center
Kerstin Bartscherer: Max Planck Institute for Molecular Biomedicine
Nicholas Katsanis: Duke University Medical Center
Erica E. Davis: Duke University Medical Center
Israel Amirav: Tel-Aviv University
Hiroshi Hamada: RIKEN Center for Biosystems Dynamics Research
Heymut Omran: University Hospital Münster

Nature Communications, 2020, vol. 11, issue 1, 1-20

Abstract: 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.

Date: 2020
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DOI: 10.1038/s41467-020-19113-0

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