RESUMO
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.
Assuntos
Cromossomos Humanos Par 11 , Proteínas do Olho/genética , Degeneração Macular/genética , Mutação de Sentido Incorreto , Sequência de Aminoácidos , Substituição de Aminoácidos , Animais , Sequência de Bases , Bestrofinas , Caenorhabditis elegans/genética , Canais de Cloreto , Mapeamento Cromossômico , Intervalos de Confiança , Primers do DNA , Éxons , Proteínas do Olho/química , Humanos , Dados de Sequência Molecular , Conformação Proteica , Recombinação Genética , Valores de Referência , Alinhamento de Sequência , Homologia de Sequência de AminoácidosRESUMO
We investigated a Swedish family with nonsyndromic progressive bilateral sensorineural hearing loss. Thirteen candidate loci for autosomal dominant nonsyndromic hearing loss were tested for linkage in this family. We found significant LOD scores (>3) for markers at candidate locus DFNA12 (11q22-q24) and suggestive LOD scores (>2) for markers at locus DFNA2 (1p32). Our results for markers on chromosome 11 narrowed down the candidate region for the DFNA12 locus. A detailed analysis of the phenotypes and haplotypes shared by the affected individuals supported the notion that two genes segregated together with hearing impairment in the family. Severely affected family members had haplotypes linked to the disease allele on both chromosomes 1 and 11, whereas individuals with milder hearing loss had haplotypes linked to the disease allele on either chromosome 1 or chromosome 11. These observations suggest an additive effect of two genes, each gene resulting in a mild and sometimes undiagnosed phenotype, but both together resulting in a more severe phenotype.
Assuntos
Cromossomos Humanos Par 11 , Cromossomos Humanos Par 1 , Perda Auditiva Neurossensorial/genética , Adulto , Audiometria , Mapeamento Cromossômico , Feminino , Lateralidade Funcional , Genes Dominantes , Ligação Genética , Marcadores Genéticos , Haplótipos , Audição/fisiologia , Perda Auditiva Neurossensorial/fisiopatologia , Humanos , Escore Lod , Masculino , Linhagem , Recombinação Genética , SuéciaRESUMO
Best macular dystrophy (BMD), also known as vitelliform macular dystrophy (VMD2; OMIM 153700), is an autosomal dominant form of macular degeneration characterized by an abnormal accumulation of lipofuscin within and beneath the retinal pigment epithelium cells. In pursuit of the disease gene, we limited the minimum genetic region by recombination breakpoint analysis and mapped to this region a novel retina-specific gene (VMD2). Genetic mapping data, identification of five independent disease-specific mutations and expression studies provide evidence that mutations within the candidate gene are a cause of BMD. The 3' UTR of the candidate gene contains a region of antisense complementarity to the 3' UTR of the ferritin heavy-chain gene (FTH1), indicating the possibility of antisense interaction between VMD2 and FTH1 transcripts.
