A nonsense mutation in a novel gene is associated with retinitis pigmentosa in a family linked to the RP1 locus

Retinitis pigmentosa (RP) represents a group of inherited human retinal dis eases which involve degeneration of photoreceptor cells resulting in visual loss and often leading to blindness. In order to identify candidate genes for the causes of these diseases, we have been studying a pool of photorece ptor-specific cDNAs isolated by subtractive hybridization of mRNAs from nor mal and photoreceptorless rd mouse retinas. One of these cDNAs was of inter est because it mapped to proximal mouse chromosome 1 in a region homologous to human 8q11-q13, the locus of autosomal dominant RP1, Therefore, using t he mouse cDNA as probe, we cloned the human cDNA (hG28) and its correspondi ng gene and mapped it near to D8S509, which lies in the RP1 locus. This gen e consists of four exons with an open reading frame of 6468 nt encoding a p rotein of 2156 amino acids with a predicted mass of 240 kDa, Given its chro mosomal localization, we screened this gene for mutations in a large family affected with autosomal dominant RP previously linked to the RP1 locus. We found an R677X mutation that co-segregated with disease in the family and is absent from unaffected members and 100 unrelated controls. This mutation is predicted to lead to rapid degradation of hG28 mRNA or to the synthesis of a truncated protein lacking similar to 70% of its original length. Our results suggest that R677X is responsible for disease in this family and th at the gene corresponding to hG28 is the RP1 gene.