The vitelliform macular dystrophy protein defines a new family of chloride channels

Abstract

Vitelliform macular dystrophy (VMD͞Best disease; MIM*153700) is an early-onset autosomal dominant disorder in which accumulation of lipofuscin-like material within and beneath the retinal pigment epithelium is associated with a progressive loss of central vision. Bestrophin, the protein product of the VMD gene, has four predicted transmembrane domains. There are multiple bestrophin homologues in the human, Drosophila, and Caenorhabditis elegans genomes, but no function has previously been ascribed to these proteins, and they show no detectable homology to other proteins of known function. Using heterologous expression, we show here that human, Drosophila, and C. elegans bestrophins form oligomeric chloride channels, and that human bestrophin is sensitive to intracellular calcium. Each of 15 missense mutations asscociated with VMD greatly reduces or abolishes the membrane current. Four of these mutant bestrophins were coexpressed with the wild type and each dominantly inhibited the wild-type membrane current, consistent with the dominant nature of the disease. These experiments establish the existence of a new chloride channel family and VMD as a channelopathy.

Focus on Molecules: Bestrophin (Best-1)

“…Since LP defects are a characteristic of Best vitelliform macular dystrophy (BMD), a disease caused by mutations in Best-1, it was hypothesized that Best-1 functions as a Ca ++ sensitive Cl − channel (CaCC) that generates the LP. Whole cell patch clamp studies of Best-1 and other bestrophins heterologously expressed in cultured cells support this hypothesis (Sun et al, 2002). Further support comes from experiments in which replacement of key amino acids appears to alter the channel ion selectivity (reviewed in Hartzell et al, 2005).…”

A novel compound heterozygous mutation in the BEST1 gene causes autosomal recessive Best vitelliform macular dystrophy

“…[1][2][3][4][5][6] BEST1 is located on chromosome 11q13 and encodes the bestrophin-1 protein that localizes to the RPE. 1,7,8 The exact function of the bestrophin protein is not completely understood. However, it has been suggested that bestrophin-1 acts as either a chloride channel or a modulator of calcium channels.…”

“…However, it has been suggested that bestrophin-1 acts as either a chloride channel or a modulator of calcium channels. 6,[8][9][10] To date, several mutations in arBVMD cases have been reported. [1][2][3]5,11,12 These include homozygous and combinations of nonsense or missense mutations.…”

Expression, localization, and functional properties of Bestrophin 3 channel isolated from mouse heart

“…Despite the significance of their conductance in many tissues, the molecular identity for the encoding channel remains unknown. Bestrophins have been identified as a novel family of Cl Ca (46) with multiple members expressed in different species (17). Several Bestrophin members have been shown to produce a calcium-activated chloride current (I ClCa ) when expressed heterologously (30, 33-36, 41, 46, 48, 49).…”