Macular Degeneration: Genetics of 4 Distrinct Phenotypes

黄斑变性：4 种不同表型的遗传学

• 批准号: 6554868
• 负责人: Radha Ayyagari
• 金额: $ 35.09万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-07-02 至 2006-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6554868
• 关键词: artificial chromosomes; autosomal dominant trait; clinical research; complementary DNA; disease /disorder onset; family genetics; gene expression; gene mutation; genetic disorder; genetic screening; genotype; human genetic material tag; human subject; linkage mapping; macular degeneration; molecular cloning; northern blottings; nucleic acid hybridization; nucleic acid sequence; phenotype; polymerase chain reaction; protein sequence; serial analysis of gene expression; sex linked trait; southern blotting

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.

该提案的重点是研究黄斑变性的生物学基础，这将通过四个大型独立谱系来观察，这些谱系具有以孟德尔方式分离的不同形式的黄斑变性。 我们正在对这些谱系进行位置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。 目前还没有针对这些使人衰弱的疾病的治疗方法。 这些基因的克隆将为从四个生物遗传学角度观察黄斑变性的过程提供机会。我们正在研究的四种形式的黄斑变性是：（1）。早发性常染色体显性萎缩性黄斑变性 (adMD)，(2)。 X连锁锥杆营养不良症（COD1），（3）。迟发性萎缩性黄斑变性 (adMD) 和 (4)。 出血性黄斑萎缩。 我们将早发型 adMD 的疾病位点映射到 6q 染色体 (6q-adMD) 上 4.9 cM 的间隔，将 COD1 的疾病位点映射到 Xpll 上约 1 cM。 我们已经排除了大多数已知的晚发性 ADMD 和出血性黄斑变性黄斑变性基因座，并且正在进行全基因组扫描以定位疾病基因。 我们构建了 6q-adMD 间隔的物理图和转录图。 目前正在对关键区域候选 EST 对应的基因进行表征。 我们将通过以下方式致力于定位克隆：(a) 通过确定谱系的其他成员并分析新标记，将疾病基因定位到一个小区间，(b) 表征候选基因，以及 (c) 筛选候选基因的突变。 一旦克隆了上述黄斑变性（MD）的基因，我们将研究黄斑变性基因与包括AMD在内的其他黄斑疾病表型之间可能的关联。由于我们无法同时处理所有四个谱系，因此计划对某些工作进行顺序分析。这项研究将鉴定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不同发病年龄和不同进展速率的机制，并将有助于开发有效的治疗方法，以减缓进展速率或延迟疾病的发病年龄。