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.

Identification of Mutations Causing Inherited Retinal Degenerations in the Israeli and Palestinian Populations Using Homozygosity Mapping

“…Furthermore, the technology of next generation sequencing (NGS) can be combined with HM for more efficient identification of mutations, as recently reported in various studies in which novel genes were identified as the cause of autosomal recessive retinal degenerations. [65][66][67][68] …”

A novel IGH@ gene rearrangement associated with CDKN2A/B deletion in young adult B-cell acute lymphoblastic leukemia

“…ARL2BP is part of the ADP ribosylation factor family of RAS-associated GTPases, and has an essential role in photoreceptor maintenance and function. Homozygous mutation in the ARL2BP gene was identified in retinitis pigmentosa, with or without situs inversus (32). In addition, overexpression of the PLLP gene has been detected in malignant pleural mesothelioma (33).…”

The Function of Arf-like Proteins ARL2 and ARL3 in Photoreceptors

“…Other interactants are the ubiquitously expressed Binder of ARL2 (BART), also called ARL2BP (Davidson et al 2013) forming a soluble complex (Sharer and Kahn 1999), PDEδ (see below), protein phosphatase 2A (PP2A) (Shern et al 2003) and UNC119 isoforms. ARL2BP mutations have been linked to recessive retinitis pigmentosa (Davidson et al 2013).…”

“…Other interactants are the ubiquitously expressed Binder of ARL2 (BART), also called ARL2BP (Davidson et al 2013) forming a soluble complex (Sharer and Kahn 1999), PDEδ (see below), protein phosphatase 2A (PP2A) (Shern et al 2003) and UNC119 isoforms. ARL2BP mutations have been linked to recessive retinitis pigmentosa (Davidson et al 2013). PDE6D (encoding PDEδ) null mutations in human cause a severe syndromic ciliopathy (Joubert syndrome) (Thomas et al 2014) and in mouse, a recessive cone-rod dystrophy (Zhang et al 2007).…”