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

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 (US)
Article number	5520
Journal	Nature communications
Volume	11
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-19113-0
State	Published - Dec 1 2020

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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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

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

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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",

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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 - 2020/12/1

Y1 - 2020/12/1

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.

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

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