The goal of our research is to identify genetic factors that account for autosomal dominant retinitis pigmentosa (adRP) and related disorders, with the long-term aim of providing clinical benefits to patients. Genetic factors include genes and mutations causing retinal disease, and genes modifying clinical expression. The causes of adRP are strikingly heterogeneous. Twelve adRP loci have been identified; of these, 7 have been cloned, and 5 have been mapped but not cloned. Mutations in 3 of the cloned genes, RDS, RHO and RP1, account for roughly 40 percent of adRP cases, whereas the remaining genes account for less than 5 percent. In addition to many genes causing adRP, different mutations in the same gene may cause different diseases, and the same mutation in different individuals may produce different symptoms, that is, additional factors modify expression. The purpose of this continuation is to clarify the causes of this heterogeneity using linkage mapping, mutation screening and analysis of modifying genes. In prior research we collected DNAs from over 300 families with dominant retinopathies, determined the disease-causing mutation in 104 of these, mapped the adRP locus in an additional 7 families, and mapped and cloned the RP1 gene. Identification of the RP1 gene was based on a large Kentucky family (RPO1) with over 120 affected members with the Arg677ter mutation, which accounts for 2 to 4 percent of adRP cases in the US. Preliminary findings suggest that 3 to 5 genes account for 95 percent of the variance in age-of-onset in RPO1, with two genes predominating. Our aims are 1) to continue ascertainment of adRP families in Texas and bordering states, 2.) to screen probands for mutations in known adRP genes, 3.) to conduct linkage testing in suitable families using markers linked to known disease loci and 4.) to test for modifying genes in RPO1. Methods include linkage mapping using capillary electrophoresis and DHPLC; mutation screening using DHPLC and sequencing; identification of potential modifying genes; and genetic analysis using LINKAGE, PAP and Loki. Continuation of this project will delineate the types and prevalences of adRP; will contribute to positional cloning projects; and may identify modifying factors which, themselves, may be targets for gene-specific therapies. A fuller understanding of the causes of dominant retinopathies will foster development of prevention and treatment.