Clinical features and mutations in patients with dominant retinitis pigmentosa-1 (RP1)

PURPOSE. To survey patients with dominant retinitis pigmentosa (RP) for mut ations in the RP1 gene to determine the spectrum of dominant mutations in t his gene, to estimate the proportion of dominant RP caused by this gene, an d to determine whether the clinical features of patients with PPI mutations differ from features of those with rhodopsin mutations. METHODS. A set of 241 patients who did not have mutations in the rhodopsin gene (based on previous work) formed the basis for the study. Of these pati ents, 117 had also been previously evaluated and were found not to carry mu tations in the RDS gene. The single-strand conformation polymorphism (SSCP) method was used to search for sequence variants, which were then directly sequenced. The relatives of selected patients were recruited for segregatio n analyses. Clinical evaluations of patients included a measurement of Snel len visual acuity, final dark adaptation thresholds, visual fields, and ERG S. Clinical data were compared with those obtained earlier from a study of 128 patients with dominant rhodopsin mutations. RESULTS. Of the 241 patients, all were screened for the most common RP1 mut ation (Arg677Ter), and 10 patients were found to have this mutation. In add ition, an evaluation of a subset of 189 patients in whom the entire coding sequence was evaluated revealed the following mutations: Gln679Ter (1 case) , Gly723Ter (2 cases), Glu729(1-bp del) (1 case), Leu762(5-bp del) (2 cases ), and Asn763(4-bp del) (1 case). All of these mutations cosegregated with RP in the families of the index patients. Nine missense mutations that were each found in six or fewer patients were encountered. The segregation of e ight of these was evaluated in the respective patients' families, and only one segregated with dominant RP. This cosegregating missense change was in cis with the nonsense mutation Gln679Ter. Although patients with RP1 mutati ons had, on average, slightly better visual acuity than patients with rhodo psin mutations, there was no statistically significant difference in final dark-adaptation thresholds, visual field diameters, or cone electroretinogr am (ERG) amplitudes. Comparably aged patients with P-PI mutations had visua l function that varied by approximately two orders of magnitude, based on v isual fields and ERG amplitudes. CONCLUSIONS. Dominant RP1 alleles typically have premature nonsense codons occurring in the last exon of the gene and would be expected to encode muta nt proteins that are only approximately one third the size of the wild-type protein, suggesting that a dominant negative effect rather than haplo-insu fficiency is the mechanism leading to RP caused by RP1 mutations. On averag e, patients with RP1 mutations have slightly better visual acuity than pati ents with dominant rhodopsin mutations; otherwise, they have similarly seve re disease. The wide range in severity among patients with RP1 mutations in dicates that other genetic or environmental factors modulate the effect of the primary mutation.