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Missense mutations in a retinal pigment epithelium protein, bestrophin-1, cause retinitis pigmentosa

By Alice E. Davidson, Ian D. Millar, Jill E. Urquhart, Rosemary Burgess-Mullan, Yusrah Shweikh, Neil Parry, James O'Sullivan, Geoffrey J. Maher, Martin McKibbin, Susan M. Downes, Andrew J. Lotery, Samuel G. Jacobson, Peter D. Brown, Graeme C.M. Black and Forbes D.C. Manson

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

Topics: RE
Year: 2009
OAI identifier: oai:eprints.soton.ac.uk:73565
Provided by: e-Prints Soton
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