Macular Degeneration: Genetics of 4 Distrinct Phenotypes

这项建议的重点是研究黄斑变性的生物学基础，通过四个大的独立的家系可以看到，这些家系以孟德尔式的方式分离不同形式的黄斑变性。我们正在对这些家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。目前还没有治疗这些令人衰弱的疾病的方法。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过程提供机会。我们正在研究的四种黄斑变性形式是：(1)。早发性常染色体显性遗传性萎缩性黄斑变性(ADMD)，(2)。X-连锁视锥-视杆细胞营养不良(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的发病基因定位在6q染色体上4.9 cM的区间(6q-ADMD)，将COD1的发病区间定位到Xpl1的1 cM左右。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基因，全基因组扫描正在进行中，以定位疾病基因。我们已经构建了6q-ADMD间隔的物理图谱和转录图谱。目前正在对与关键区域中候选EST对应的基因进行鉴定。我们将致力于位置克隆：(A)通过确定更多的家系成员和分析新的标记，将疾病基因定位到较小的间隔，(B)确定候选基因的特征，以及(C)筛选候选基因的突变。一旦上述黄斑变性基因(S)被克隆，我们将研究黄斑变性基因与包括黄斑变性在内的其他表型黄斑疾病之间的可能关联。因为我们不能同时对所有四个家系进行研究，所以一些工作计划进行顺序分析。这项研究将导致鉴定导致选择性黄斑变性的基因突变。这些基因将有助于了解上述退行性疾病发病年龄和进展速度变化的机制，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推迟发病年龄。

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.