The mutation spectrum of the bestrophin protein - functional implications

Abstract

Best's macular dystrophy (BMD), also known as vitelliform macular degeneration type 2 (VMD2; OMIM 153700), is an autosomal dominant form of macular degeneration with mainly juvenile onset. BMD is characterized by the accumulation of lipofuscin within and beneath the retinal pigment epithelium. The gene causing the disease has been localized to 11q13 by recombination breakpoint mapping. Recently, we have identified the causative gene encoding a protein named bestrophin, and mutations have been found mainly to affect residues that are conserved from a family of genes in Caenorhabditis elegans. The function of bestrophin is so far unknown, and no reliable predictions can be made from sequence comparisons. We have investigated the bestrophin gene in 14 unrelated Swedish, Dutch, Danish, and Moroccan families affected with BMD and found eight new mutations. Including the previously published mutations, 15 different missense mutations have now been detected in 19 of the 22 families with BMD investigated by our laboratory. Interestingly, the mutations cluster in certain regions, and no nonsense mutations or mutations causing frame-shifts have been identified. Computer simulations of the structural elements in the bestrophin protein show that this protein is probably membrane bound, with four putative transmembrane regions.

Frequency, Genotype, and Clinical Spectrum of Best Vitelliform Macular Dystrophy: Data From a National Center in Denmark

“…8 Two additional Danish families were reported by Bakall et al in 1999 (Table 1). 11 Patients with Best disease identified in the present study demonstrated a variable clinical appearance, ranging from precipitate-like alterations at the level of the photoreceptor outer segments to choroidal neovascularization. The findings thus exceeded those reported recently in asymptomatic patients with Best disease, in whom a subtle thickening was demonstrated by SD-OCT between the retinal pigment epithelium and the photoreceptors.…”

“…8,[11][12][13][14][15][16] In the present study, sequencing analysis of all BEST1 exons revealed heterozygous missense changes that are likely pathogenic in all eight analyzed families as well as one sporadic case (Fig. 2, Supplemental material at AJO.com or Supplemental Fig.…”

Mutations in the VMD2 gene are associated with juvenile-onset vitelliform macular dystrophy (Best disease) and adult vitelliform macular dystrophy but not age-related macular degeneration

“…6,[11][12][13][14][15][16] Recently, the VMD2 gene was identified by positional cloning, and thus far 29 different disease-related mutations have been described. [17][18][19][20] VMD2 is RPE-specific and is comprised of 11 exons coding for a 585 amino acid protein of unknown function. The identification of the disease gene now facilitates research aimed at understanding the pathogenetic mechanism underlying Best disease.…”

Best's macular dystrophy in Australia: phenotypic profile and identification of novel BEST1 mutations

“…This, however, is not inconsistent with previously identified mutations (p.Gly135Ser). 41,42 Despite specific clustering of VMD mutations within BEST1, clear genotype-phenotype correlations are yet to be established for VMD. However, a recent study by a Dutch group purported a severe disease phenotype in one family with a Ala10Val mutation.…”