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，这将通过四种大型独立的谱系来观察，具有不同形式的黄斑变性，以孟德尔的方式隔离。 我们正在对这些血统的位置克隆和候选基因分析进行，目前强调早期发作萎缩黄斑变性。 目前尚无治疗这些使人衰弱的疾病。 这些基因的克隆将提供一个从四个生物遗传学角度来研究黄斑变性过程的机会。我们正在研究的黄斑变性的四种形式是：（1）。早期发作常染色体显性萎缩性黄斑变性（ADMD），（2）。 X连锁的锥杆营养不良（COD1），（3）。晚期发作萎缩性黄斑变性（ADMD）和（4）。 出血性黄斑萎缩。 我们将疾病基因座映射为早期发作AMDD，在6q（6q-ADMD）上的4.9 cm间隔和cod1的间隔为4.9 cm。 我们排除了大多数已知的黄斑变性基因座，用于晚期发病和出血性黄斑变性，并且正在进行基因组范围的扫描以定位疾病基因。 我们已经构建了6Q-ADMD间隔的物理和成绩单图。 目前正在进行与关键区域中候选EST相对应的基因的表征。 我们将通过：（a）通过确定血统的其他成员并分析新标记，（b）表征候选基因的其他成员，以及（c）筛选突变的候选基因，将疾病基因定位在一个小间隔中。 一旦克隆了上述黄斑变性（S）（MD）的基因，我们将研究黄斑变性基因与包括AMD在内的黄斑疾病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种血统，所以计划进行一些工作进行顺序分析。这项研究将导致鉴定基因突变，从而导致黄斑选择性变性。 这些基因将有助于理解上述退化的变化年龄和变化速度的可变年龄的基础机制，并将有助于开发有效的治疗方法以减慢进展速度或延迟疾病的发作年龄。