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.
| Original language | English |
|---|---|
| Pages (from-to) | 321-329 |
| Number of pages | 9 |
| Journal | American Journal of Human Genetics |
| Volume | 93 |
| Issue number | 2 |
| DOIs | |
| State | Published - 8 Aug 2013 |
| Externally published | Yes |
Bibliographical note
Funding Information:We acknowledge the cooperation and help provided by the family members in this study. We are grateful to colleagues who referred affected individuals to us at Moorfields Eye Hospital and those who contributed to the assembly of large panels of probands, particularly Bev Scott, Genevieve Wright, Sophie Devery, Michel Michaelides, Tony Moore, Eva Lenassi, Graham Holder, and Tony Robson. We acknowledge the nationally commissioned Royal Brompton Hospital Primary Ciliary Dyskinesia diagnostic service led by Claire Hogg and Steve Rothery at the Imperial College Imaging Facility (London, UK). We acknowledge Alexy Obolensky for retinal-imaging assistance. We are grateful to Nick Cowan, Karl Matter, and Jane Evans for providing antibodies or plasmids. We acknowledge the following sources of funding: RP Fighting Blindness, Fight for Sight, Moorfields Eye Hospital Special Trustees, the Moorfields Eye Charity, the National Institute for Health Research (NIHR) (Moorfields Eye Hospital and Institute of Ophthalmology [London, UK]), the Foundation Fighting Blindness (BR-GE-0510-0490-HUJ to D.S.), a Yedidut 1 research grant (to E.B.), European Community’s Seventh Framework Programme FP7/2009/241955 (SYSCILIA), and the FAUN Foundation (Nuremburg, Germany) (to U.W.). V.P. is partly funded by the UK Medical Research Council (G1001158) and by the NIHR Biomedical Research Centre based at Moorfields Eye Hospital NHS Foundation Trust and Institute of Ophthalmology at University College London. R.A.K. is supported in part by a grant from the National Institutes of Health (GM090158).