Mutations in the pre-mRNA splicing factor gene PRPC8 in autosomal dominantretinitis pigmentosa (RP13)

Retinitis pigmentosa (RP) is a genetically heterogeneous disorder character ized by progressive degeneration of the peripheral retina leading to night blindness and loss of visual fields. With an incidence of approximately 1 i n 4000, RIP can be inherited in X-linked, autosomal dominant or autosomal r ecessive modes. The RP13 locus for autosomal dominant RIP (adRP) was placed on chromosome 17p13.3 by linkage mapping in a large South African adRP fam ily. Using a positional cloning and candidate gene strategy, we have identi fied seven different missense mutations in the splicing factor gene PRPC8 i n adRP families. Three of the mutations cosegregate within three RP13 linke d families including the original large South African pedigree, and four ad ditional mutations have been identified in other unrelated adRP families. T he seven mutations are clustered within a 14 codon stretch within the last exon of this large 7 kb transcript. The altered amino acid residues at the C-terminus exhibit a high degree of conservation across species as diverse as humans, Arabidopsis and trypanosome, suggesting that some functional sig nificance is associated with this part of the protein. These mutations in t his ubiquitous and highly conserved splicing factor offer compelling eviden ce for a novel pathway to retinal degeneration.