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

Nat Commun. 2020 Nov 2;11(1):5520. doi: 10.1038/s41467-020-19113-0.

Gerard W Dougherty ¹, Katsutoshi Mizuno ², Tabea Nöthe-Menchen ¹, Yayoi Ikawa ² ³, Karsten Boldt ⁴, Asaf Ta-Shma ⁵, Isabella Aprea ¹, Katsura Minegishi ² ³, Yuan-Ping Pang ⁶, Petra Pennekamp ¹, Niki T Loges ¹, Johanna Raidt ¹, Rim Hjeij ¹, Julia Wallmeier ¹, Huda Mussaffi ⁷ ⁸, Zeev Perles ⁵, Orly Elpeleg ⁹, Franziska Rabert ¹⁰, Hidetaka Shiratori ³, Stef J Letteboer ¹¹, Nicola Horn ⁴, Samuel Young ¹², Timo Strünker ¹², Friederike Stumme ¹, Claudius Werner ¹, Heike Olbrich ¹, Katsuyoshi Takaoka ² ³, Takahiro Ide ², Wang Kyaw Twan ², Luisa Biebach ¹, Jörg Große-Onnebrink ¹, Judith A Klinkenbusch ¹, Kavita Praveen ¹³, Diana C Bracht ¹, Inga M Höben ¹, Katrin Junger ⁴, Jana Gützlaff ¹, Sandra Cindrić ¹, Micha Aviram ¹⁴, Thomas Kaiser ¹, Yasin Memari ¹⁵ ¹⁶, Petras P Dzeja ¹⁷, Bernd Dworniczak ¹⁸, Marius Ueffing ⁴, Ronald Roepman ¹¹, Kerstin Bartscherer ¹⁰ ¹⁹ ²⁰, Nicholas Katsanis ¹³ ²¹ ²², Erica E Davis ¹³ ²¹ ²², Israel Amirav ²³ ²⁴, Hiroshi Hamada ² ³, Heymut Omran ²⁵

Affiliations

1 Department of General Pediatrics, University Hospital Münster, Münster, Germany.
2 RIKEN Center for Biosystems Dynamics Research, Kobe, Japan.
3 Developmental Genetics Group, Graduate School of Frontier Biosciences, Osaka University, Osaka, Japan.
4 Institute for Ophthalmic Research, Molecular Biology of Retinal Degenerations and Medical Bioanalytics, University of Tübingen, Tübingen, Germany.
5 Department of Pediatric Cardiology, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
6 Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, USA.
7 Schneider Children's Medical Center, Prtach-Tiqva, Israel.
8 Sackler Faculty of Medicine, Tel Aviv University, Ramat, Aviv, Israel.
9 Department of Genetics, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
10 Max Planck Research Group on Stem Cells & Regeneration, Max Planck Institute for Molecular Biomedicine, Münster, Germany.
11 Department of Human Genetics and Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, the Netherlands.
12 Centre of Reproductive Medicine and Andrology, University Hospital Münster, University of Münster, Münster, Germany.
13 Center for Human Disease Modeling, Duke University Medical Center, Durham, NC, USA.
14 Soroka Medical Center, Beer-Sheva, Israel.
15 Department of Medical Genetics, Addenbrooke's Hospital, Cambridge, UK.
16 MRC Cancer Unit, Hutchison / MRC Research Centre, Cambridge, UK.
17 Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN, USA.
18 Department of Human Genetics, University of Münster, Münster, Germany.
19 Medical Faculty, University of Münster, Münster, Germany.
20 Hubrecht Institute, Utrecht, the Netherlands.
21 Advanced Center for Translational and Genetic Medicine (ACT-GeM), Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, IL, USA.
22 Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
23 Pulmonology Unit, Dana-Dwek Children's Hospital, Tel-Aviv University, Tel-Aviv, Israel.
24 Department of Pediatrics, University of Alberta, Edmonton, Canada.
25 Department of General Pediatrics, University Hospital Münster, Münster, Germany. [email protected].

PMID: 33139725 DOI: 10.1038/s41467-020-19113-0

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.

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