Mutations in ARL2BP, a Protein Required for Ciliary Microtubule Structure, Cause Syndromic Male Infertility in Humans and Mice

Authors

Abigal R. Moye, West Virginia University
Nicola Bedoni, University of Lausanne
Jessica G. Cunningham, West Virginia University
Urikhan Sanzhaeva, West Virginia University
Eric S. Tucker, West Virginia University
Peter Mathers, West Virginia University
Virginie G. Peter, University of Lausanne
Mathieu Quinodoz, University of Lausanne
Liliana P. Paris, Instituto de Oftalmologia Dr Gama Pinto, Lisbon, Portugal
Luisa Coutinho-Santos, Instituto de Oftalmologia Dr Gama Pinto, Lisbon, Portugal
Pedro Camacho, Instituto de Oftalmologia Dr Gama Pinto, Lisbon, Portugal
Madeleine G. Purcell, Randolph-Macon College
Abbie C. Winkelmann, Randolph-Macon College
James A. Foster, Randolph-Macon College
Elena N. Pugacheva, West Virginia University
Carlo Rivolta, University of Lausanne, University of Leicester, Institute of Molecular and Clinical Ophthalmology Basel,
Visvanathan Ramamurthy, West Virginia UniversityFollow

Author ORCID Identifier

https://orcid.org/0000-0002-3698-7156

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https://orcid.org/0000-0002-3174-8113

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https://orcid.org/0000-0003-2957-7770

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https://orcid.org/0000-0001-8157-9568

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https://orcid.org/0000-0002-2986-5652

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https://orcid.org/0000-0002-0733-9950

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Document Type

Article

Publication Date

2019

Department/Program/Center

Ophthalmology

Abstract

Cilia are evolutionarily conserved hair-like structures with a wide spectrum of key biological roles, and their dysfunction has been linked to a growing class of genetic disorders, known collectively as ciliopathies. Many strides have been made towards deciphering the molecular causes for these diseases, which have in turn expanded the understanding of cilia and their functional roles. One recently-identified ciliary gene is ARL2BP, encoding the ADP-Ribosylation Factor Like 2 Binding Protein. In this study, we have identified multiple ciliopathy phenotypes associated with mutations in ARL2BP in human patients and in a mouse knockout model. Our research demonstrates that spermiogenesis is impaired, resulting in abnormally shaped heads, shortened and mis-assembled sperm tails, as well as in loss of axonemal doublets. Additional phenotypes in the mouse included enlarged ventricles of the brain and situs inversus. Mouse embryonic fibroblasts derived from knockout animals revealed delayed depolymerization of primary cilia. Our results suggest that ARL2BP is required for the structural maintenance of cilia as well as of the sperm flagellum, and that its deficiency leads to syndromic ciliopathy.

Digital Commons Citation

Moye, Abigal R.; Bedoni, Nicola; Cunningham, Jessica G.; Sanzhaeva, Urikhan; Tucker, Eric S.; Mathers, Peter; Peter, Virginie G.; Quinodoz, Mathieu; Paris, Liliana P.; Coutinho-Santos, Luisa; Camacho, Pedro; Purcell, Madeleine G.; Winkelmann, Abbie C.; Foster, James A.; Pugacheva, Elena N.; Rivolta, Carlo; and Ramamurthy, Visvanathan, "Mutations in ARL2BP, a Protein Required for Ciliary Microtubule Structure, Cause Syndromic Male Infertility in Humans and Mice" (2019). Faculty & Staff Scholarship. 1881.
https://researchrepository.wvu.edu/faculty_publications/1881

Source Citation

Moye, A. R., Bedoni, N., Cunningham, J. G., Sanzhaeva, U., Tucker, E. S., Mathers, P., Peter, V. G., Quinodoz, M., Paris, L. P., Coutinho-Santos, L., Camacho, P., Purcell, M. G., Winkelmann, A. C., Foster, J. A., Pugacheva, E. N., Rivolta, C., & Ramamurthy, V. (2019). Mutations in ARL2BP, a protein required for ciliary microtubule structure, cause syndromic male infertility in humans and mice. PLOS Genetics, 15(8), e1008315. https://doi.org/10.1371/journal.pgen.1008315

Comments

© 2019 Moye et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.