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

Journal article

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.

Authors: Davidson, A; Millar, I; Urquhart, J; Burgess-Mullan, R; Shweikh, Y

• Publication status: Published
• Journal: American journal of human genetics
• Volume: 85
• Issue: 5
• Pages: 581-592
• Publication date: 2009-11-01
• DOI: 10.1016/j.ajhg.2009.09.015
• EISSN: 1537-6605
• ISSN: 0002-9297
• Language: English
• Keywords: Humans; Chloride Channels; Mutation, Missense; Protein Isoforms; Pedigree; Female; Retinal Pigment Epithelium; Eye Proteins; Polymorphism, Single Nucleotide; Amino Acid Sequence; Male; Lod Score; Chromosomes, Human, Pair 11; Genes, Recessive; Genetic Linkage; Kidney; Sequence Homology, Amino Acid; Molecular Sequence Data; Homozygote; Retinitis Pigmentosa; Conserved Sequence; Nuclear Family; Genes, Dominant; Cell Line; Exons