Journal
AMERICAN JOURNAL OF HUMAN GENETICS
Volume 85, Issue 5, Pages 581-592Publisher
CELL PRESS
DOI: 10.1016/j.ajhg.2009.09.015
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Funding
- National Eye Research Centre [SCIAD 051]
- Fight for Sight
- British Retinitis Pigmentosa Society
- Macula Vision Research Foundation
- Manchester Biomedical Research Centre
- Manchester Academic Health Sciences Centre (MAHSC)
- National Institute for Health Research (NIHR)
- Biotechnology and Biological Sciences Research Council
- Wellcome Trust
- University of Manchester Strategic Fund
- National Institute for Health Research [NF-SI-0507-10094] Funding Source: researchfish
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Bestrophin-1 is preferentially expressed at the basolateral membrane of the retinal pigmented epithelium (RPE) of the retina. Mutations in the BEST] 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.1205T) 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.
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