Camiel J F Boon 1, B Jeroen Klevering, Bart P Leroy, Carel B Hoyng, Jan E E Keunen, Anneke I den Hollander | Prog Retin Eye Res | 2009 May |28(3) | Pages 187-205 | doi: 10.1016/j.preteyeres.2009.04.002
Abstract
Bestrophin-1 is an integral membrane protein, encoded by the BEST1 gene, which is located in the basolateral membrane of the retinal pigment epithelium. The bestrophin-1 protein forms a Ca(2+) activated Cl(-) channel and is involved in the regulation of voltage-dependent Ca(2+) channels. In addition, bestrophin-1 appears to play a role in ocular development. Over 120 different human BEST1 mutations have been described to date, associated with a broad range of ocular phenotypes. The purpose of this review is to describe this spectrum of phenotypes, which includes Best vitelliform macular dystrophy and adult-onset foveomacular vitelliform dystrophy, autosomal dominant vitreoretinochoroidopathy, the MRCS (microcornea, rod-cone dystrophy, cataract, posterior staphyloma) syndrome, and autosomal recessive bestrophinopathy. The genotype-phenotype correlations that are observed in association with BEST1 mutations are discussed. In addition, in vitro studies and animal models that clarify the pathophysiological mechanisms are reviewed.
Introduction
Best vitelliform macular dystrophy (BVMD) is among the most frequently encountered autosomal dominant (AD) retinal dystrophies and predominantly affects the macula. BVMD was the first disease shown to be caused by mutations in the BEST1 gene, which encodes the bestrophin-1 protein that localizes to the retinal pigment epithelium (RPE) (Petrukhin et al., 1998). Subsequent studies showed that BEST1 gene mutations may also be found in patients with adult-onset foveomacular vitelliform dystrophy (AFVD) (Allikmets et al., 1999, Kramer et al., 2000, Seddon et al., 2001). BVMD and AFVD are related phenotypes with abnormalities that are generally restricted to the macula. However, more widespread ocular abnormalities may arise in association with specific BEST1 gene mutations that cause AD vitreoretinochoroidopathy (ADVIRC) and AD MRCS (microcornea, rod-cone dystrophy, early-onset cataract, and posterior staphyloma) syndrome (Reddy et al., 2003, Yardley et al., 2004, Michaelides et al., 2006, Burgess et al., 2008a). The same applies to autosomal recessive bestrophinopathy (ARB), the human null phenotype of bestrophin-1, which is associated with high hyperopia and shallow anterior chambers (Burgess et al., 2008b). Therefore, ADVIRC, MRCS syndrome, as well as ARB belong to a spectrum of diseases with abnormal ocular development that extends beyond the retina.
In this paper, we aim to review the characteristics of the BEST1 gene and its multifunctional protein product bestrophin-1, with an emphasis on the broad spectrum of ocular phenotypes associated with mutations in this gene. The effects of different BEST1 mutations are discussed, as well as their genotype–phenotype correlations. Available in vitro and animal models are addressed, as well as histopathologic observations in BEST1-related diseases, that expand our insight in the pathogenesis. Finally, perspectives on future therapeutic strategies are discussed.
The BEST1 gene
The human BEST1 gene was identified in 1998 by Petrukhin and colleagues (Petrukhin et al., 1998). BEST1 is located on chromosome 11q12, spans 15 kilobases of genomic DNA and contains 11 exons of which 10 are protein-coding (Marquardt et al., 1998, Petrukhin et al., 1998). Eight years later, the mouse ortholog was characterized (Kramer et al., 2004). An alternative name for BEST1 is VMD2, but the Human Genome Organisation and the Mouse Genome Database nomenclature committees recently recommended
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