DNA Linkage Studies of Degenerative Retinal Diseases

描述（由申请人提供）：本持续项目的目的是鉴定常染色体显性视网膜色素变性（adRP）的基因和突变。AdRP，像其他形式的遗传性视网膜疾病一样，是一组复杂的疾病，有多种原因、不同的症状和不同的后果。例如，已知17种不同基因的突变会导致adRP。然而，已知基因的突变占adRP家族的不到60%，因此在遗传水平上理解adRP还有很长的路要走。

DESCRIPTION (provided by applicant): The purpose of this continuing project is to identify the genes and mutations causing autosomal dominant retinitis pigmentosa (adRP). AdRP, like other forms of inherited retinal disease, is a complex set of disorders, with multiple causes, variable symptoms, and differing consequences. For example, mutations in seventeen distinct genes are known to cause adRP. However, mutations in the known genes account for less than 60% of adRP families, thus there is a long way to go before adRP is understood at a genetic level. Our goal is to identify the genes and mutations affecting the remaining 40% of families. We hypothesize that the remaining cases will be caused by 1) mutations in novel adRP genes and 2) mutations in known genes that are not detected by standard screening methods or mutations that are not recognized as pathogenic. It is also clear that some families with "adRP" actually have more complex modes of inheritance, i.e., digenic or X-linked dominant disease. The challenge is to cut through this complexity to identify the genes that cause the largest fraction of cases. To achieve this goal we have established a step-wise, systematic approach to patient ascertainment, mutation testing, linkage mapping, and candidate gene screening. Patients and families are ascertained through our clinical collaborators and enrolled in our studies. We evaluate each patient and family to select the most effective staging of tests to determine the underlying gene and mutation. Patients and families are re-evaluated at each subsequent stage. Suitable families become part of our growing cohort of well-characterized adRP families, now numbering 215. DNAs from probands are tested by rapid screening methods to detect common mutations in known adRP genes. Those without mutations become part of an expanding panel of samples for finding new disease genes and novel mutations in known genes. Families with multiple, accessible, affected individuals are enrolled for linkage mapping to test for linkage to known dominant RP genes (to uncover mutations not detected earlier) and, if the known genes are excluded, for genome-wide linkage testing (to find new adRP genes). These families are our "Gene Discovery Cohort". Our current set of linkage markers for dominant RP genes is targeted to all of the known genes and loci, several additional candidate genes, and X-linked genes which may cause clinical symptoms in carrier females. Genome-wide linkage testing will be done by SNP typing using the Affymetrix GeneChip Human Mapping 10K Array, available through the Univ. of Texas MD Anderson Cancer Center Microarray Core Facility, Houston, Texas. Finally, probands from families that are not large enough for linkage mapping become part of our "Mutation Testing Panel". As new genes are identified, or as new approaches to testing become available, this panel is screened to replicate findings, determine prevalences, and evaluate new concepts.