PKD1 GENE

常染色体显性遗传性多囊肾病是一种常见的遗传病 影响1/1000人的疾病，通常导致严重的 肾功能衰竭或中风的发病率。先前的位置克隆 研究人员已经定义了一个小于500千碱基的遗传间隔 包含PKD1基因，并从该区域鉴定出23个cDNA； 这项提议的长期目标是精确定位和研究基因和 导致蛋白酪氨酸激酶1的突变。最初，三核苷酸重复来自 将分析与疾病相关的扩张，这些扩张已经 在临床上引起类似ADPKD的疾病。全新的多态 标记将用于连锁研究。聚合酶扩增的基因座 将在囊肿源性组织中检查链式反应以寻找丢失的 杂合性。如果通过研究不稳定的方法不能确定基因 要素，该战略将采用系统的方法，如单一的 链构象多态分析(SSCP)用于区域扫描 突变的抄本。PKD1基因序列分析、基因组学分析 结构，并执行表情模式。表型 突变之间的相关性将被调查。第二阶段 项目将取决于基因的性质和预测的基因产物。 人们计划进行实验，以开发抗体来研究空间 以及基因产物的时间分布。此外，该项目 考虑体外和体内的发展或确认 多囊肾病异常模型。

Autosomal dominant polycystic kidney disease (ADPKD) is a common genetic disorder that affects 1/1000 persons, often leading to significant morbidity from renal failure or stroke. Previous positional cloning efforts have defined a genetic interval of less than 500 kilobases containing the PKD1 gene and identified 23 cDNAs from the region; the long-term aim of this proposal is to pinpoint and study the gene and mutations that cause PKD1. Initially, trinucleotide repeats from the interval will be analyzed for disease-related expansions, which have been shown to cause disorders clinically similar to ADPKD. All new polymorphic markers will be used in linkage studies. Loci amplified by the polymerase chain reaction will be examined in cyst-derived tissues for loss of heterozygozity. If the gene is not identified by studying unstable elements, the strategy will employ systematic methods such as single- stranded conformation polymorphism analysis (SSCP) to scan regional transcripts for mutations. Analysis of the PKD1 gene sequence, genomic structure, and expression pattern will be performed. Phenotypic correlations of mutations will be investigated. The second phase of the project will depend on the nature of the gene and predicted gene product. Experiments are contemplated to develop antibodies to study the spatial and temporal distribution of the gene product. In addition, the project contemplates the development or confirmation of in vitro and in vivo models of polycystic kidney disease abnormalities.