The mutation spectrum of the bestrophin protein - functional implications

Best's macular dystrophy (BMD), also known as vitelliform macular degenerat ion type 2 (VMD2; OMIM 153700), is an autosomal dominant form of macular de generation with mainly juvenile onset. BMD is characterized by the accumula tion of lipofuscin within and beneath the retinal pigment epithelium. The g ene causing the disease has been localized to 11q13 by recombination breakp oint mapping. Recently, we have identified the causative gene encoding a pr otein named bestrophin, and mutations have been found mainly to affect resi dues that are conserved from a family of genes in Caenorhabditis elegans. T he function of bestrophin is so far unknown, and no reliable predictions ca n be made from sequence comparisons. We have investigated the bestrophin ge ne in 14 unrelated Swedish, Dutch, Danish, and Moroccan families affected w ith BMD and found eight new mutations. Including the previously published m utations, 15 different missense mutations have now been detected in 19 of t he 22 families with BMD investigated by our laboratory. Interestingly, the mutations cluster in certain regions, and no nonsense mutations or mutation s causing frame-shifts have been identified. Computer simulations of the st ructural elements in the bestrophin protein show that this protein is proba bly membrane bound, with four putative transmembrane regions.