Macular Degeneration: Genetics of 4 Distrinct Phenotypes

本提案的重点是研究黄斑变性的生物学基础，这将通过四个大的独立谱系看到，黄斑变性的不同形式以孟德尔方式分离。我们正在对这些谱系进行定位克隆和候选基因分析，目前的重点是早发性萎缩性黄斑变性。目前还没有治疗这些使人衰弱的疾病的方法。克隆这些基因将提供一个机会，看看黄斑变性的过程从四个生物学遗传学的角度。我们正在研究的黄斑变性的四种形式是：(1)。早发常染色体显性萎缩性黄斑变性（adMD），(2)。X-linked锥杆营养不良（COD1），(3)。迟发性萎缩性黄斑变性（adMD）和(4)。出血性黄斑萎缩。我们将早发性adMD的疾病位点定位在6q染色体（6q-adMD）上的4.9 cM间隔，将COD1定位在Xpll上的约1 cM间隔。我们已经排除了大多数已知的迟发性adMD和出血性黄斑变性的黄斑变性位点，并且正在进行全基因组扫描以定位疾病基因。我们已经构建了6q-adMD区间的物理图谱和转录本图谱。关键区域候选ESTs对应基因的鉴定目前正在进行中。我们将通过以下方式进行定位克隆：(a)通过确定家系的其他成员和分析新的标记，将疾病基因定位到小范围内；(b)表征候选基因；(c)筛选候选突变基因。一旦克隆出上述黄斑变性（MD）的基因，我们将研究黄斑变性基因与黄斑病变（包括AMD）的其他表型形式之间的可能关联。因为我们不能同时处理所有四个谱系，所以一些工作计划用于顺序分析。本研究将有助于识别导致黄斑选择性变性的基因突变。这些基因将有助于理解上述变性的可变发病年龄和可变进展速度的机制，并将有助于开发有效的治疗方法，以减缓疾病的进展速度或延迟疾病的发病年龄。

The focus of this proposal is to study the biological basis of macular degeneration as will be seen through four large independent pedigrees with distinct forms of macular degeneration segregating in Mendelian fashion. We are in the process of positional cloning and candidate gene analysis of these pedigrees, with current emphasis on early onset atrophic macular degeneration. Currently no treatment is available for these debilitating diseases. Cloning of these genes will provide an opportunity to look at the process of degeneration of macula from four biological genetic perspectives. The four forms of macular degeneration we are studying are: (1). Early onset autosomal dominant atrophic macular degeneration (adMD), (2). X-linked cone-rod dystrophy (COD1), (3). Late onset atrophic macular degeneration (adMD) and (4). Hemorrhagic macular atrophy. We mapped the disease locus for early onset adMD to a 4.9 cM interval on chromosome 6q (6q-adMD) and for COD1 to about 1 cM at Xpll. We have excluded most of the known macular degeneration loci for late onset adMD and hemorrhagic macular degeneration, and a genome wide scan to localize the disease genes is in progress. We have constructed physical and transcript maps of the 6q-adMD interval. Characterization of genes corresponding to candidate ESTs in the critical region is currently in progress. We will work toward positional cloning by: (a) localizing the disease gene to a small interval by ascertaining additional members of the pedigrees and analyzing new markers, (b) Characterizing candidate genes, and (c) Screening candidate genes for mutations. Once the gene(s) for above macular degeneration(s) (MD) is cloned, we will study the possible association between the macular degeneration gene and other phenotypic forms of macular diseases including AMD. Because we can not work on all four pedigrees simultaneously, some of the work is planned for sequential analysis. This study will result in identification of gene mutations causing selective degeneration of macula. These genes will help in understanding the mechanism underlying the variable age of onset and variable rate of progression of the above degenerations and will assist in developing effective treatments either to slow the rate of progression or to delay the age of onset of the disease.