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

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 dise...

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Published in:	PLoS genetics Vol. 15; no. 8; p. e1008315
Main Authors:	Moye, Abigail R, Bedoni, Nicola, Cunningham, Jessica G, Sanzhaeva, Urikhan, Tucker, Eric S, Mathers, Peter, Peter, Virginie G, Quinodoz, Mathieu, Paris, Liliana P, Coutinho-Santos, Luísa, Camacho, Pedro, Purcell, Madeleine G, Winkelmann, Abbie C, Foster, James A, Pugacheva, Elena N, Rivolta, Carlo, Ramamurthy, Visvanathan
Format:	Journal Article
Language:	English
Published:	United States Public Library of Science 19-08-2019 Public Library of Science (PLoS)
Subjects:	ADP-ribosylation factor Adult Animals Biochemistry Biology Biology and Life Sciences Cardiovascular disease Carrier Proteins - genetics Cilia Cilia - pathology Ciliopathies - genetics Ciliopathies - pathology Defects Depolymerization Disease Models, Animal Embryo fibroblasts Embryos Female Flagella Funding Gene mutation Genes Genetic aspects Genetic disorders Genetically modified animals Genetics Humans Identification and classification Infertility Infertility, Male - genetics Infertility, Male - pathology Inversion Male Male infertility Medicine and Health Sciences Membrane Transport Proteins - genetics Mice Mice, Knockout Microtubules - metabolism Middle Aged Motility Mutation Neurosciences Observations Pedigree Phenotypes Photophobia - genetics Photophobia - pathology Photoreceptors Physiological aspects Protein binding Proteins Research and Analysis Methods Sperm Sperm Motility - genetics Sperm Tail - pathology Spermatogenesis Spermatogenesis - genetics Spermiogenesis Supervision Syndrome Transcription Factors United States West Virginia United States > US Portugal Switzerland
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Summary:	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.
Bibliography:	new_version ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 The authors have declared that no competing interests exist.
ISSN:	1553-7404 1553-7390 1553-7404
DOI:	10.1371/journal.pgen.1008315