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 常染色体显性遗传性视网膜色素变性(ADRP)的遗传因素 以及相关的疾病，长期目标是为 病人。遗传因素包括导致视网膜疾病的基因和突变， 和改变临床表达的基因。Adrp的原因是惊人的。 异质的。已鉴定出12个ADRP基因座；其中7个已被 克隆，5个已定位但未克隆。其中3个克隆的基因发生突变 RDS、RHO和RP1基因约占ADRP病例的40%，而 剩下的基因所占比例不到5%。除了许多基因之外 引起adrp，同一基因的不同突变可能导致不同的 疾病，而相同的突变在不同的个体中可能产生不同的 症状，也就是额外的因素改变了表情。 本文继续的目的是阐明这种异质性的原因。 利用连锁作图、突变筛选和修饰基因分析。在……里面 之前的研究我们收集了300多个家庭的DNA 视网膜病变，确定了其中104例的致病突变，绘制了地图 对另外7个家系中的adrp基因进行了定位和克隆。 RP1基因的鉴定是基于一个肯塔基州大家族(RPO1) 超过120名受Arg677ter突变影响的成员，占2%到 美国4%的ADRP病例。初步调查结果显示，有3到5个 基因解释了RPO1发病年龄差异的95%，有两个 占主导地位的基因。我们的目标是1)继续确定ADRP家族 在德克萨斯州和邻近的州，2)筛查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联和4.)以检测RPO1中的修饰基因。 方法包括利用毛细管电泳法和DHPLC法进行连锁定位； 用DHPLC法和测序法筛选突变；潜在的鉴定 修改基因；利用连锁、PAP和Loki进行遗传分析。 这一项目的继续将描述ADRP的类型和流行情况； 将为位置克隆项目做出贡献；并可能确定修改 这些因子本身可能是基因特异性治疗的靶点。更饱满的人 了解主导性视网膜病变的原因将促进发展 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.