GENETIC CHARACTERIZATION OF ALPORT SYNDROME

阿尔波特综合征的遗传特征

• 批准号: 3239217
• 负责人: CURTIS L ATKIN
• 金额: $ 16.41万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-03-01 至 1992-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3239217
• 关键词: DNA; Goodpasture's syndrome; autosomal dominant trait; biopsy; chromosome deletion; congenital deafness; gel electrophoresis; genetic counseling; genetic disorder; genetic disorder diagnosis; genetic mapping; genetic markers; genetic transcription; genotype; glomerulonephritis; human population genetics; kidney transplantation; linkage mapping; major histocompatibility complex; molecular pathology; nephritis; nucleic acid probes; nucleic acid sequence; sex chromosomes; skin

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.

Alport综合征（AS）是一组异质性的 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的病因不明， 被认为涉及GBM结构蛋白的缺陷。 疾病 频率大于或等于1/5000。 影响最大 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 不同人群AS的表型异质性 运动障碍包括眼缺陷、血小板增多症和/或 进行性感音神经性耳聋， 肾衰竭 基因型异质性包括 常染色体以及更明确的X连锁 传承 本申请的长期目标是 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 开发 我们建议更好地定义表型， 利用肾炎与X-连锁限制性片段长度的连锁 多态性标记（RFLP），以精确定位染色体 在23个X连锁AS表型中， 来自犹他州的肯塔基州。 我们已经证明了两种类型的AS 犹他州三个最大的家族与DNA有着松散的联系 在X染色体长臂中间的探针。 我们 建议构建一个高分辨率的遗传连锁图， X的区域与目前可用的探测器和我们计划 发展。 通过绘制AS基因的遗传图谱， 明确的区域，我们希望测试遗传的假设， X连锁AS的异质性，以改善遗传过程 诊断和咨询这种疾病，并制定一个 鉴定和克隆缺陷的方法 基因。 我们还建议确定X染色体是否 缺失导致AS：缺失的存在会改善 快速鉴定正常基因的前景， 在AS失踪