GENETIC STUDIES OF AUTOSOMAL DOMINANT POLYCYSTIC KIDNEY DISEASE

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 虽然在了解ADPKD的遗传学和临床属性方面取得了重大进展，但关于ADPKD家族之间或家族内基因型和表型之间关系的信息很少。 两个ADPKD基因，16号染色体上的PKD 1和4号染色体上的PKD 2已经被关闭，并且推导出的蛋白质结构使得能够对ADPKD类型进行遗传鉴别。 许多研究报道了ADPKD突变在家族内和家族间的表达变化。 这项研究的目的是确定哪些遗传因素导致了这种变异，然后确定所涉及的基因或DNA序列。 ADPKD的许多肾外表现出家族间和家族内的显著差异，表明其他基因在确定特定临床特征方面很重要。 该项目的目标是将我们独特的ADPKD家族研究人群的数据与我们的遗传分析结合起来，从而进一步了解ADPKD。 我们预计将研究700个家庭，其中包括2,500名来自所有民族的人。 将对先前招募的ADPKD家族成员或参与他汀类药物治疗对ADPKD儿童疾病进展的影响研究的受试者进行基因检测。 参与者将被要求同意采集血液样本进行基因检测和肾功能检查。 我们将分析野生型基因的影响和基因组筛选基因修饰剂收集的数据。 这些知识将促进目前对ADPKD的理解，从而使未来的患者护理得到改善。 虽然在过去的十年中已经了解了很多关于ADPKD的遗传学和疾病的表型表现，但关于ADPKD家族之间或家族内基因型和表型之间关系的信息很少。两个ADPKD基因，16号染色体上的ADPKD 1和4号染色体上的ADPKD 2已被克隆，推导出蛋白质结构，并在两个基因中鉴定出许多突变。许多研究报道了ADPKD突变在家族内和家族间的表达存在极大差异。 这项研究的目的是确定不同的遗传因素在多大程度上促成了这种变异，然后确定所涉及的基因或DNA序列。 我们已经阐明了许多肾外表现的疾病，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性，表明其他基因在确定特定的临床特征中是重要的。 有明确的证据表明，基因座异质性是临床变异的主要来源，因为PKD 2是比PKD 1温和得多的疾病形式。 很少或没有证据表明特异性PKD突变与临床表达之间存在关系。 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遗传性多囊肾病（ADPKD）家族人口与最近的遗传学突破相结合，以使我们对这种疾病的理解取得实质性进展。 我们希望在5年项目期结束时研究500个家庭，其中包括来自所有民族的2000人。 将对以下三组之一的参与者进行基因检测：未受影响的高危亲属，受影响的家庭成员和ADPKD家族中未受影响的亲属。已知受影响的参与者将被要求同意进行血液采样以进行基因检测和肾功能检测。 我们将分析野生型基因的影响和基因组筛选基因修饰剂收集的数据。 从我们对ADPKD的理解的实质性进展（这是本研究的目标）来看，临床治疗的进展和改进将随之而来。

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 significant advances have been made in understanding the genetics and clinical attributes of ADPKD there is little information regarding the relationship between genotype and phenotype between or within ADPKD families. Both ADPKD genes, PKD1 on chromosome 16 and PKD2 on chromosome 4 have been closed and the protein structures deduced enabling genetic discrimination of ADPKD type. Many studies have reported variation in the expression ADPKD mutation within and between families. The purpose of this study is to determine which genetic factors contribute to this variation, and then to identify the genes or DNA sequences that are involved. Many of the extra renal manifestations of ADPKD demonstrate substantial inter- and intra-familial variability, indicating other genes are important in determining specific clinical characteristics. The goal of this project is to couple data from our uniquely well-studied population of ADPKD families with our genetic analyses thus furthering understanding of ADPKD. We expect to study 700 families that include 2,500 individuals from all ethnic groups. Genetic testing will be done on members of previously recruited ADPKD families or affected subjects participating in The Effect of Statin Therapy on Disease Progression in Children with ADPKD study. 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. This knowledge will advance current understanding of ADPKD thus allowing future improvement of patient care. 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.