Disease expression of RP1 mutations causing autosomal dominant retinitis pigmentosa

PURPOSE. TO determine the disease expression in heterozygotes for mutations in the RP1 gene, a newly identified cause of autosomal dominant retinitis pigmentosa (adRP). METHODS. Screening strategies were used to detect disease-causing mutations in the RP1 gene, and detailed studies of phenotype were performed in a sub set of the detected RP1 heterozygotes using electroretinography (ERG), psyc hophysics, and optical coherence tomography (OCT). RESULTS. Seventeen adRP families had heterozygous RP1 changes. Thirteen fam ilies had the Arg677ter mutation, whereas four others had one of the follow ing: Pro658 (1-bp del), Ser747 (1-bp del), Leu762-763 (5-bp del), and Tyr10 53 (1-bp del). In Arg677ter RP1 heterozygotes, there was regional retinal v ariation in disease, with the far peripheral inferonasal retina being most vulnerable; central and superior temporal retinal regions were better prese rved. The earliest manifestation of disease was rod dysfunction, detectable as reduced rod ERG photoresponse maximum amplitude, even in heterozygotes with otherwise normal clinical, functional, and OCT cross-sectional retinal imaging results. At disease stages when cone abnormalities were present, t here was greater rod than cone dysfunction. Patients with the RP1 frameshif t mutations showed similarities in phenotype to those with the Arg677ter mu tation. CONCLUSIONS. Earliest disease expression of RP1 gene mutations causing adRP involves primarily rod photoreceptors, and there is a gradient of vulnerab ility of retinopathy with more pronounced effects in the inferonasal periph eral retina. At other disease stages, cone function is also affected, and s evere retina-wide degeneration can occur. The nonpenetrance or minimal dise ase expression in some Arg677ter mutation-positive heterozygotes suggests i mportant roles for modifier genes or environmental factors in RP1-related d isease.