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Mutations in ARL2BP, a protein required for ciliary microtubule structure, cause syndromic male infertility in humans and mice

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posted on 15.05.2020, 11:36 by Abigail R Moye, Nicola Bedoni, Jessica G Cunningham, Urikhan Sanzhaeva, Eric S Tucker, Peter Mathers, Virginie G Peter, Mathieu Quinodoz, Liliana P Paris, Luisa Coutinho-Santos, Pedro Camacho, Madeleine G Purcell, Abbie C Winkelmann, James A Foster, Elena N Pugacheva, Carlo Rivolta, Visvanathan Ramamurthy
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 ADPRibosylation 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.

Funding

This work was supported by USA National Institutes of Health Grants (https://www.nih.gov) R01 EY028035 (to VR), R01 EY025536 (to VR and Peter Stoilov), R21 EY027707 (to VR), and West Virginia Lions and Lions Club International Foundation (http://wvlions.org/programs.html) to VR, as well as grants from the Swiss National Science Foundation (http://www.snf.ch/en/Pages/default.aspx) to CR [grant number:176097], and grants from USA National Science Foundation (https://www.nsf.gov) MRI #1229184 to JAF. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

History

Citation

Moye AR, Bedoni N, Cunningham JG, Sanzhaeva U, Tucker ES, Mathers P, et al. (2019) Mutations in ARL2BP, a protein required for ciliary microtubule structure, cause syndromic male infertility in humans and mice. PLoS Genet 15(8): e1008315. https://doi.org/10.1371/journal.pgen.1008315

Version

VoR (Version of Record)

Published in

PLOS GENETICS

Volume

15

Issue

8

Pagination

(28)

Publisher

PUBLIC LIBRARY SCIENCE

issn

1553-7404

eissn

1553-7404

Acceptance date

17/07/2019

Copyright date

2019

Available date

19/08/2019

Publisher version

https://journals.plos.org/plosgenetics/article?rev=2&id=10.1371/journal.pgen.1008315

Language

English