GENETIC STUDIES OF AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。虽然在过去的十年中，关于ADPKD的遗传学和疾病的表型表现已经了解了很多，但关于ADPKD家族之间或内部的基因和表型之间的关系的信息很少。位于16号染色体上的ADPKD基因和位于4号染色体上的ADPKD2基因已经被克隆，蛋白质结构推导，并鉴定了这两个基因的大量突变。许多研究已经报道了ADPKD突变在家庭内部和家庭之间的表达极端差异。这项研究的目的是确定不同的遗传因素对这种变异的影响程度，然后确定涉及的基因或DNA序列。我们已经阐明了这种疾病的许多肾脏以外的表现，包括肝囊性疾病、心脏瓣膜异常、颅内动脉瘤和其他。表型表现出显著的家族间和家族内变异，表明其他基因在决定特定的临床特征方面也很重要。有明确的证据表明，基因座异质性是临床变异的一个主要来源，因为PKD2是一种比PKD1温和得多的疾病形式。很少或没有证据表明特定的PKD突变与临床表现之间的关系。遗传学项目的总体目标是将我们独特的庞大且经过充分研究的常染色体显性多囊肾病(ADPKD)家族群体与最近的基因突破结合起来，以带来我们对这种疾病的理解的实质性进展。我们预计到五年项目期结束时将研究500个家庭，其中包括来自所有族裔群体的2000人。将对以下三个群体之一的参与者进行基因测试：未受影响的高危亲属、受影响的家庭成员和ADPKD家庭中未受影响的亲属。已知受影响的参与者将被要求同意对血液样本进行基因测试和肾功能检查。我们将分析收集的数据以了解野生型基因的影响，并分析基因组中是否有基因修饰物。我们对ADPKD的理解取得了实质性的进展，这是本研究的目标，临床治疗的进步和改进也将随之而来。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Although much has been learned in the last decade about both the genetics of ADPKD and the phenotypic manifestations of the disease, there is very little information regarding the relationship between genotype and phenotype between or within ADPKD families. Both ADPKD genes, ADPKD1 on chromosome 16 and ADPKD2 on chromosome 4 have been cloned, the protein structures deduced, and numerous mutations in both genes identified. Many studies have reported extreme variation in the expression of ADPKD mutations within and between families. The purpose of this study is to determine the extent to which different genetic factors contribute to this variation, and then to identify the genes or DNA sequences that are involved. We have elucidated many of the extra renal manifestations of the disease including hepatic cystic disease, cardiac valve abnormalities, intracranial aneurysms and others. The phenotypes demonstrate substantial inter- and intra-familial variability, indicating other genes are important in determining specific clinical characteristics. There is clear evidence that locus heterogeneity is a major source of clinical variation in that PKD2 is a much milder form of the disease than PKD1. There is little or no evidence for a relationship between the specific PKD mutation and clinical expression. The overall goal of the genetics project is to couple our uniquely large and well-studied population of autosomal dominant polycystic kidney disease (ADPKD) families with the recent genetic breakthroughs to bring about substantial advances in our understanding of this disease. We expect to study 500 families by the end of the 5-year project period which includes 2000 individuals from all ethnic groups. Genetic testing will be done on participants in one of the three following groups: unaffected at-risk relatives, affected family members and unaffected relatives in ADPKD families. Known affected participants will be asked to consent to blood sampling for genetic testing and kidney function. We will analyze the data collected for effects of the wild-type gene, and the genome screen for gene modifiers. From the substantial advances in our understanding of ADPKD which is the goal of this study, clinical treatment advances and improvements will follow.