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; Heymut Omran

doi:10.1038/s41467-020-19113-0

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 › Article › peer-review

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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 language	English
Article number	5520
Journal	Nature Communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-19113-0
State	Published - 2 Nov 2020
Externally published	Yes

Bibliographical note

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

Funding

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.

Funders	Funder number
Hadassah
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 Diseases	R01DK072301
Seventh Framework Programme	241,955
European Commission	262,055
Deutsche Forschungsgemeinschaft	OM6/11, OM6/10, BA4044/3-1, OM6/8, OM6/7, OM6/9
Japan Society for the Promotion of Science	24113004
Japan Science and Technology Corporation	13417760
ZonMw	91216051
Max-Planck-Gesellschaft
Interdisziplinäres Zentrum für Klinische Forschung, Universitätsklinikum Würzburg	Om/015/16, Om2/009/12, DFG CRU326

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Dougherty, G. W., Mizuno, K., Nöthe-Menchen, T., Ikawa, Y., Boldt, K., Ta-Shma, A., Aprea, I., Minegishi, K., Pang, Y. P., Pennekamp, P., Loges, N. T., Raidt, J., Hjeij, R., Wallmeier, J., Mussaffi, H., Perles, Z., Elpeleg, O., Rabert, F., Shiratori, H., ... Omran, H. (2020). CFAP45 deficiency causes situs abnormalities and asthenospermia by disrupting an axonemal adenine nucleotide homeostasis module. Nature Communications, 11(1), Article 5520. https://doi.org/10.1038/s41467-020-19113-0

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title = "CFAP45 deficiency causes situs abnormalities and asthenospermia by disrupting an axonemal adenine nucleotide homeostasis module",

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.",

author = "Dougherty, {Gerard W.} and Katsutoshi Mizuno and Tabea N{\"o}the-Menchen and Yayoi Ikawa and Karsten Boldt and Asaf Ta-Shma and Isabella Aprea and Katsura Minegishi and Pang, {Yuan Ping} and Petra Pennekamp and Loges, {Niki T.} and Johanna Raidt and Rim Hjeij and Julia Wallmeier and Huda Mussaffi and Zeev Perles and Orly Elpeleg and Franziska Rabert and Hidetaka Shiratori and Letteboer, {Stef J.} and Nicola Horn and Samuel Young and Timo Str{\"u}nker and Friederike Stumme and Claudius Werner and Heike Olbrich and Katsuyoshi Takaoka and Takahiro Ide and Twan, {Wang Kyaw} and Luisa Biebach and J{\"o}rg Gro{\ss}e-Onnebrink and Klinkenbusch, {Judith A.} and Kavita Praveen and Bracht, {Diana C.} and H{\"o}ben, {Inga M.} and Katrin Junger and Jana G{\"u}tzlaff and Sandra Cindri{\'c} and Micha Aviram and Thomas Kaiser and Yasin Memari and Dzeja, {Petras P.} and Bernd Dworniczak and Marius Ueffing and Ronald Roepman and Kerstin Bartscherer and Nicholas Katsanis and Davis, {Erica E.} and Israel Amirav and Hiroshi Hamada and Heymut Omran",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s).",

year = "2020",

month = nov,

day = "2",

doi = "10.1038/s41467-020-19113-0",

language = "אנגלית",

volume = "11",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Research",

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Dougherty, GW, Mizuno, K, Nöthe-Menchen, T, Ikawa, Y, Boldt, K, Ta-Shma, A, Aprea, I, Minegishi, K, Pang, YP, Pennekamp, P, Loges, NT, Raidt, J, Hjeij, R, Wallmeier, J, Mussaffi, H, Perles, Z, Elpeleg, O, Rabert, F, Shiratori, H, Letteboer, SJ, Horn, N, Young, S, Strünker, T, Stumme, F, Werner, C, Olbrich, H, Takaoka, K, Ide, T, Twan, WK, Biebach, L, Große-Onnebrink, J, Klinkenbusch, JA, Praveen, K, Bracht, DC, Höben, IM, Junger, K, Gützlaff, J, Cindrić, S, Aviram, M, Kaiser, T, Memari, Y, Dzeja, PP, Dworniczak, B, Ueffing, M, Roepman, R, Bartscherer, K, Katsanis, N, Davis, EE, Amirav, I, Hamada, H & Omran, H 2020, 'CFAP45 deficiency causes situs abnormalities and asthenospermia by disrupting an axonemal adenine nucleotide homeostasis module', Nature Communications, vol. 11, no. 1, 5520. https://doi.org/10.1038/s41467-020-19113-0

TY - JOUR

T1 - CFAP45 deficiency causes situs abnormalities and asthenospermia by disrupting an axonemal adenine nucleotide homeostasis module

AU - Dougherty, Gerard W.

AU - Mizuno, Katsutoshi

AU - Nöthe-Menchen, Tabea

AU - Ikawa, Yayoi

AU - Boldt, Karsten

AU - Ta-Shma, Asaf

AU - Aprea, Isabella

AU - Minegishi, Katsura

AU - Pang, Yuan Ping

AU - Pennekamp, Petra

AU - Loges, Niki T.

AU - Raidt, Johanna

AU - Hjeij, Rim

AU - Wallmeier, Julia

AU - Mussaffi, Huda

AU - Perles, Zeev

AU - Elpeleg, Orly

AU - Rabert, Franziska

AU - Shiratori, Hidetaka

AU - Letteboer, Stef J.

AU - Horn, Nicola

AU - Young, Samuel

AU - Strünker, Timo

AU - Stumme, Friederike

AU - Werner, Claudius

AU - Olbrich, Heike

AU - Takaoka, Katsuyoshi

AU - Ide, Takahiro

AU - Twan, Wang Kyaw

AU - Biebach, Luisa

AU - Große-Onnebrink, Jörg

AU - Klinkenbusch, Judith A.

AU - Praveen, Kavita

AU - Bracht, Diana C.

AU - Höben, Inga M.

AU - Junger, Katrin

AU - Gützlaff, Jana

AU - Cindrić, Sandra

AU - Aviram, Micha

AU - Kaiser, Thomas

AU - Memari, Yasin

AU - Dzeja, Petras P.

AU - Dworniczak, Bernd

AU - Ueffing, Marius

AU - Roepman, Ronald

AU - Bartscherer, Kerstin

AU - Katsanis, Nicholas

AU - Davis, Erica E.

AU - Amirav, Israel

AU - Hamada, Hiroshi

AU - Omran, Heymut

PY - 2020/11/2

Y1 - 2020/11/2

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=85094920875&partnerID=8YFLogxK

U2 - 10.1038/s41467-020-19113-0

DO - 10.1038/s41467-020-19113-0

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C2 - 33139725

AN - SCOPUS:85094920875

SN - 2041-1723

VL - 11

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 5520

ER -

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

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