Missense Mutations in a Retinal Pigment Epithelium Protein, Bestrophin-1, Cause Retinitis Pigmentosa |
| |
Authors: | Alice E. Davidson Jill E. Urquhart Yusrah Shweikh James O'Sullivan Martin McKibbin Andrew J. Lotery Peter D. Brown Forbes D.C. Manson |
| |
Affiliation: | 1 Genetic Medicine, The University of Manchester, Manchester Academic Heath Science Centre, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK 2 Faculty of Life Sciences, The University of Manchester, Manchester, UK 3 National Genetics Reference Laboratory, St. Mary's Hospital, Manchester, UK 4 Manchester Royal Eye Hospital, Central Manchester University Hospitals NHS Foundation Trust, Manchester, UK 5 St. James's University Hospital, Leeds, UK 6 Oxford Eye Hospital, John Radcliffe Hospital, Oxford, UK 7 University of Southampton, Southampton, UK 8 Department of Ophthalmology, Scheie Eye Institute, University of Pennsylvania, PA, USA |
| |
Abstract: | Bestrophin-1 is preferentially expressed at the basolateral membrane of the retinal pigmented epithelium (RPE) of the retina. Mutations in the BEST1 gene cause the retinal dystrophies vitelliform macular dystrophy, autosomal-dominant vitreochoroidopathy, and autosomal-recessive bestrophinopathy. Here, we describe four missense mutations in bestrophin-1, three that we believe are previously unreported, in patients diagnosed with autosomal-dominant and -recessive forms of retinitis pigmentosa (RP). The physiological function of bestrophin-1 remains poorly understood although its heterologous expression induces a Cl−-specific current. We tested the effect of RP-causing variants on Cl− channel activity and cellular localization of bestrophin-1. Two (p.L140V and p.I205T) produced significantly decreased chloride-selective whole-cell currents in comparison to those of wild-type protein. In a model system of a polarized epithelium, two of three mutations (p.L140V and p.D228N) caused mislocalization of bestrophin-1 from the basolateral membrane to the cytoplasm. Mutations in bestrophin-1 are increasingly recognized as an important cause of inherited retinal dystrophy. |
| |
Keywords: | |
本文献已被 ScienceDirect 等数据库收录! |
|