RP1 protein truncating mutations predominate at the RP1 adRP locus

PURPOSE. Recent reports have shown that the autosomal dominant retinitis pi gmentosa (adRP) phenotype linked to the pericentric region of chromosome 8 is associated with mutations in a gene designated RP1. Screening of the who le gene in a large cohort of patients has not been undertaken to date. To a ssess the involvement and character of RP1 mutations in adRP, the gene was screened in a panel of 266 unrelated patients of British origin and a Pakis tani family linked to this locus. METHODS. Patients exhibiting the adRP phenotype were screened for mutations in the four exons of the RP1 gene by heteroduplex analysis and direct sequ encing. Linkage of the Pakistani family was achieved using microsatellite m arkers. Polymerase chain reaction (PCR) products were separated by nondenat uring polyacrylamide gel electrophoresis. Alleles were assigned to individu als, which allowed calculation of LOD scores. Microsatellite marker haploty ping was used to determine ancestry of patients carrying the same mutation. RESULTS. In the 266 British patients and 1 Pakistani family analyzed, 21 lo ss-of-function mutations and 7 amino acid substitutions were identified, so me of which may also be disease-causing. The mutations, many of which were deletion or insertion events, were clustered in the 5' end of exon 4. Most mutations resulted in a premature termination codon in the mRNA. Haplotype analysis of nine patients carrying an R677X mutation suggested that these p atients are not ancestrally related. CONCLUSIONS. RP1 mutations account for 8% to 10% of the mutations in our co hort of British patients. The most common disease-causing mechanism is dedu ced to be one involving the presence of a truncated protein. Mutations in R P1 have now been described in adRP patients of four ethnically diverse popu lations. The different disease haplotype seen in the nine patients carrying the same mutation suggests that this mutation has arisen independently man y times, possibly due to a mutation hot spot in this part of the gene.