title: Mutations in ARL2BP, encoding ADP-ribosylation-factor-like 2 binding protein, cause autosomal-recessive retinitis pigmentosa.
abstract: Retinitis pigmentosa (RP) is a genetically heterogeneous retinal degeneration characterized by photoreceptor death, which results in visual failure. Here, we used a combination of homozygosity mapping and exome sequencing to identify mutations in ARL2BP, which encodes an effector protein of the small GTPases ARL2 and ARL3, as causative for autosomal-recessive RP (RP66). In a family affected by RP and situs inversus, a homozygous, splice-acceptor mutation, c.101-1G>C, which alters pre-mRNA splicing of ARLBP2 in blood RNA, was identified. In another family, a homozygous c.134T>G (p.Met45Arg) mutation was identified. In the mouse retina, ARL2BP localized to the basal body and cilium-associated centriole of photoreceptors and the periciliary extension of the inner segment. Depletion of ARL2BP caused cilia shortening. Moreover, depletion of ARL2, but not ARL3, caused displacement of ARL2BP from the basal body, suggesting that ARL2 is vital for recruiting or anchoring ARL2BP at the base of the cilium. This hypothesis is supported by the finding that the p.Met45Arg amino acid substitution reduced binding to ARL2 and caused the loss of ARL2BP localization at the basal body in ciliated nasal epithelial cells. These data demonstrate a role for ARL2BP and ARL2 in primary cilia function and that this role is essential for normal photoreceptor maintenance and function.
authors.affiliation: UCL Institute of Ophthalmology, London EC1V 9EL, UK.
authors.forename: Alice E
authors.initials: AE
authors.lastname: Davidson
authors.forename: Nele
authors.initials: N
authors.lastname: Schwarz
authors.forename: Lina
authors.initials: L
authors.lastname: Zelinger
authors.forename: Gabriele
authors.initials: G
authors.lastname: Stern-Schneider
authors.forename: Amelia
authors.initials: A
authors.lastname: Shoemark
authors.forename: Benjamin
authors.initials: B
authors.lastname: Spitzbarth
authors.forename: Menachem
authors.initials: M
authors.lastname: Gross
authors.forename: Uri
authors.initials: U
authors.lastname: Laxer
authors.forename: Jacob
authors.initials: J
authors.lastname: Sosna
authors.forename: Panagiotis I
authors.initials: PI
authors.lastname: Sergouniotis
authors.forename: Naushin H
authors.initials: NH
authors.lastname: Waseem
authors.forename: Robert
authors.initials: R
authors.lastname: Wilson
authors.forename: Richard A
authors.initials: RA
authors.lastname: Kahn
authors.forename: Vincent
authors.initials: V
authors.lastname: Plagnol
authors.forename: Uwe
authors.initials: U
authors.lastname: Wolfrum
authors.forename: Eyal
authors.initials: E
authors.lastname: Banin
authors.forename: Alison J
authors.initials: AJ
authors.lastname: Hardcastle
authors.forename: Michael E
authors.initials: ME
authors.lastname: Cheetham
authors.forename: Dror
authors.initials: D
authors.lastname: Sharon
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Webster
mesh_terms: D020727:ADP-Ribosylation Factors / Q000235:genetics* / Q000378:metabolism; D000328:Adult; D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism; D005260:Female; D019204:GTP-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D005808:Genes, Recessive; D006720:Homozygote; D006801:Humans; D008297:Male; D026901:Membrane Transport Proteins; D051379:Mice; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D010786:Photoreceptor Cells / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D012174:Retinitis Pigmentosa / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D014157:Transcription Factors
chemical_list: C485676:ARL2BP protein, human; C121938:Arl2bp protein, mouse; D002352:Carrier Proteins; D026901:Membrane Transport Proteins; D014157:Transcription Factors; C485819:Arl2 protein, mouse; D019204:GTP-Binding Proteins; C490248:Arl3 protein, mouse; D020727:ADP-Ribosylation Factors