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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 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.

Original publication

DOI

10.1016/j.ajhg.2009.09.015

Type

Journal article

Journal

Am J Hum Genet

Publication Date

11/2009

Volume

85

Pages

581 - 592

Keywords

Amino Acid Sequence, Cell Line, Chloride Channels, Chromosomes, Human, Pair 11, Conserved Sequence, Exons, Eye Proteins, Female, Genes, Dominant, Genes, Recessive, Genetic Linkage, Homozygote, Humans, Kidney, Lod Score, Male, Molecular Sequence Data, Mutation, Missense, Nuclear Family, Pedigree, Polymorphism, Single Nucleotide, Protein Isoforms, Retinal Pigment Epithelium, Retinitis Pigmentosa, Sequence Homology, Amino Acid