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 journalArticlepeer-review

33 Scopus citations


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
Article number5520
JournalNature Communications
Issue number1
StatePublished - 2 Nov 2020
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2020, The Author(s).


We thank the study individuals for participation, the German patient group ‘Kartagener Syndrom und Primaere Ciliaere Dyskinesie e.V.’, Holstiege Farm (Roxel, Münster), K. Wohlgemuth, A. Robbers, C. Westermann, B. Lechtape, M. Herting, D. Ernst, L. Schwiddessen, F. J. Seesing, S. Helms and C. Hartmann for technical support, A. Sabo, S. Dugan-Rocha, D. Muzny, and R. Gibbs for assisting targeted (ciliaproteome) NGS, R. Durbin and A.K. Kokocinski for WES, and Kyosuke Shinohara (Tokyo University of Agriculture and Technology) and Koji Okamoto (The University of Tokyo) for software of PIV analysis. We thank D.R. Mitchell for critically reviewing the manuscript and C.B. Lindemann for discussing insights on ADP. This research was supported by the generous support of the Victoria Popkin Fund through Hadassah, the Women’s Zionist Organization of America, Inc. to A.T., the Deutsche Forschungsgemeinschaft (DFG) OM6/7, OM6/8, OM6/9, OM6/10, OM6/11, Interdisziplinaeres Zentrum für Klinische For-schung, Muenster IZKF (Om2/009/12 and Om/015/16), and BESTCILIA 305,404 grant to H.Omran, DFG CRU326 to T.S. and H. Omran, the European Commission FP7/ 2007–2013 grant 262,055 to Y.M. and H. Omran as a Transnational Access project of the European Sequencing and Genotyping Infrastructure, the European Union FP7 program SYSCILIA grant 241,955 to R.R., M.U., N.K. and H. Omran, the Netherlands Organisation for Health Research and Development (ZonMW, #91216051) to R.R., the CREST Japan Science and Technology Corporation 13417760 and Japan Society for the Promotion of Science 24113004 grants to H.H., the Max Planck Society EXC 1003-CiM (Cluster of Excellence Cells in Motion) and German Research Foundation BA4044/3-1 grants to K.B., and U.S. National Institutes of Health grant DK072301 to N.K. and E.E.D. N.K. is a distinguished George W. Brumley Professor.

FundersFunder number
Interdisziplinaeres Zentrum für Klinische For-schung
Victoria Popkin Fund
Women’s Zionist Organization of America, Inc.
National Institutes of Health
National Institute of Diabetes and Digestive and Kidney DiseasesR01DK072301
Seventh Framework Programme241,955
European Commission262,055
Deutsche ForschungsgemeinschaftOM6/11, OM6/10, BA4044/3-1, OM6/8, OM6/7, OM6/9
Japan Society for the Promotion of Science24113004
Japan Science and Technology Corporation13417760
Interdisziplinäres Zentrum für Klinische Forschung, Universitätsklinikum WürzburgOm/015/16, Om2/009/12, DFG CRU326


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