DNA Linkage Studies of Degenerative Retinal Diseases

描述（由申请人提供）：我们研究的目标是确定 常染色体显性视网膜色素变性（adRP）的遗传因素 和相关疾病，其长期目标是为以下患者提供临床益处： 患者遗传因素包括导致视网膜疾病的基因和突变， 和修饰临床表达的基因。adRP的原因是惊人的 异质的已经鉴定了12个adRP基因座;其中，7个已被鉴定为 克隆，5个已映射但未克隆。3个克隆中的突变 RDS、RHO和RP 1基因占adRP病例的大约40%，而 其余的基因占不到百分之五。除了许多基因 引起adRP，同一基因的不同突变可能导致不同的 同样的突变在不同的个体中可能产生不同的 症状，也就是说，额外的因素改变表达。 这种延续的目的是澄清这种异质性的原因 利用连锁作图、突变筛选和修饰基因的分析。在 在之前的研究中，我们收集了300多个显性遗传的家庭的DNA， 视网膜病变，确定了其中104例的致病突变， 在另外7个家系中检测到adRP基因座，并对RP 1基因进行了定位和克隆。 RP 1基因的鉴定基于一个大的肯塔基州家族（RPO 1）， 超过120名受影响的成员与Arg 677 ter突变，占2至 在美国，有4%的adRP病例。初步调查结果显示，3至5名 RPO 1发病年龄的变异中，基因占95%，其中两个基因 基因主导我们的目标是：1）继续确定adRP家族 在得克萨斯州和接壤的国家，2。筛选先证者的已知基因突变， adRP基因，3.）利用标记在合适的家系中进行连锁检测 与已知的疾病基因座相关，以及4.）来检测RPO 1中的基因修饰 方法包括毛细管电泳和DHPLC的连锁图谱; 使用DHPLC和测序进行突变筛查;鉴定潜在的 修饰基因;和使用LINKAGE、PAP和Loki的遗传分析。 该项目的继续将描述adRP的类型和患病率; 将有助于定位克隆项目;并可能识别修改 这些因子本身可能是基因特异性疗法的靶点。更全面 了解显性视网膜病变的原因将促进 预防和治疗。

DESCRIPTION (provided by applicant): 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.