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PLoS Genet. 2019 Aug 19;15(8):e1008315. doi: 10.1371/journal.pgen.1008315. eCollection 2019 Aug.

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

Author information

1
Department of Ophthalmology, West Virginia University, Morgantown, United States of America.
2
Department of Biochemistry, West Virginia University, Morgantown, United States of America.
3
Department of Computational Biology, Unit of Medical Genetics, University of Lausanne, Lausanne, Switzerland.
4
Rockefeller Neurosciences Institute, West Virginia University, Morgantown, WV, United States of America.
5
Department of Ophthalmology, Instituto de Oftalmologia Dr Gama Pinto, Lisbon, Portugal.
6
Department of Biology, Randolph-Macon College, Ashland, VA, United States of America.
7
Department of Genetics and Genome Biology, University of Leicester, Leicester, United Kingdom.
8
Clinical Research Center, Institute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland.
9
Department of Ophthalmology, University Hospital Basel, Switzerland.

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.

PMID:
31425546
PMCID:
PMC6715254
DOI:
10.1371/journal.pgen.1008315
[Indexed for MEDLINE]
Free PMC Article

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