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GENETIC CHARACTERIZATION OF ALPORT SYNDROME

阿尔波特综合征的遗传特征

基本信息

批准号：
3239219
负责人：
CURTIS L ATKIN
金额：
$ 13.5万
依托单位：
UNIVERSITY OF UTAH
依托单位国家：
美国
项目类别：
财政年份：
1988
资助国家：
美国
起止时间：
1988-03-01 至 1993-02-28
项目状态：
已结题

项目摘要

Alport syndrome (AS) denominates a heterogeneous group of hereditary chronic progressive glomerulonephritides that are characterized by similar nephrologic symptoms and by similar progressive degeneration of glomerular capillary epithelial basement membranes (GBM). The etiology of AS is unknown but is thought to involve defects of GBM structural proteins. Disease frequency is greater than or equal to 1 in 5,000. Most affected males experience end-stage renal disease (ESRD), and they account for 2-4% of males that receive dialysis or kidney transplantation. Phenotypic heterogeneity of AS among different kindreds includes eye defects, thrombocytopathia, and/or progressive sensorineural deafness, and rate of progression of renal failure. Genotypic heterogeneity is reported to include autosomal as well as the more clearly established X-linked inheritance. The long-term objective of this application is to determine the genetic and biochemical bases of AS in order that specific and effective treatments or prevention might be developed. We propose to better define the phenotypes, and to use linkage of nephritis to X-linked restriction fragment length polymorphic markers (RFLPs) to precisely map the chromosomal locus for each of three X-linked AS phenotypes found among 23 Utah kindreds. We have already shown that two types of AS among the three largest Utah kindreds are loosely linked to DNA probes in the middle of the long arm of the X chromosome. We propose to construct a high-resolution genetic linkage map of this region of the X with currently available probes and ones we plan to develop. By mapping the AS gene(s) within this genetically well-defined region, we expect to test the hypothesis of genetic heterogeneity for X-linked AS, to improve the process of genetic diagnosis and counseling for this disease, and to develop an approach to the identification and cloning of the defective gene(s). We also propose to determine whether X-chromosome deletions cause AS: the existence of deletions would improve the prospects for rapid identification of the normal gene(s) that are missing in AS.

阿尔波特综合征(AS)是指一组不同类型的遗传性慢性进行性肾小球肾炎以相似的肾病症状和相似的肾小球毛细血管上皮进行性变性基底膜(GBM)。AS的病因尚不清楚，但被认为与GBM结构蛋白的缺陷有关。疾病频率大于或等于1/5,000。受影响最大的男性患有终末期肾病(ESRD)，他们占接受透析或肾脏治疗的男性的2-4% 移植。不同亚型间AS的表型异质性家系包括眼睛缺陷、血小板增多症和/或进行性感音神经性耳聋和进展率肾功能衰竭。据报道，基因异质性包括常染色体以及更明确地建立的X连锁继承。此应用程序的长期目标是确定AS的遗传和生化基础，以便具体和有效的治疗或预防可能是发展起来的。我们建议更好地定义表型，并利用肾炎与X-连锁限制性片段长度的连锁用于精确定位染色体的多态标记(RFLP) 在23个X-连锁AS表型中发现了每一个的基因座犹他州的亲戚。我们已经展示了两种类型的AS 在犹他州最大的三个家族中，与DNA的联系很松散位于X染色体长臂中间的探针。我们建议构建这一高分辨率的遗传连锁图谱带当前可用的探测器和我们计划的探测器的X区域去发展。通过将AS基因(S)定位在该基因内定义明确的区域，我们希望检验遗传假说针对X连锁AS的异质性，改善遗传过程对这种疾病的诊断和咨询，并制定一种缺陷基因的鉴定与克隆方法探讨基因(S)。我们还建议确定X染色体是否删除的原因是：删除的存在将改善正常基因(S)的快速鉴定前景在AS中失踪。