Genetics of Autosomal Dominant Polycystic Liver Disease

描述（由申请人提供）：我们的研究计划集中在实现人类多囊肝和肾病的全面分子理解。我们的目标是发现有效治疗患者的新范例。我们采取了一种方法，首先通过定位克隆发现疾病基因，以了解疾病的遗传基础，然后进行功能研究，以了解细胞发病机制。在目前的资助下，我们招募了孤立性常染色体显性遗传性多囊肝病（ADPLD; MIM 174050）患者，并完成了对该疾病的全面临床表征。我们建立了一个基因座，PLD 1的遗传连锁，并发现了疾病基因，PRKCSH。我们在6号染色体上鉴定了ADPLD的第二个基因座，并将人SEC 63鉴定为PLD 2。在我们的队列中，这些基因的突变占ADPLD先证者的约25%，并表明至少有一个额外的位点，PLD 3，ADPLD。PRKCSH编码葡萄糖苷酶II（GIIB）的B亚基，GIIB是一种参与ER中蛋白质成熟和质量控制的葡萄糖修整酶。SEC 63编码ER蛋白易位机制的组分，其与GII协同作用以实现完整膜或分泌糖蛋白的适当拓扑结构和折叠。该提案旨在通过发现ADPLD中涉及的其他基因，通过确定ADPLD中囊肿形成是否需要两次命中，以及通过定义ER中蛋白质成熟与胆管上皮中初级纤毛正常功能之间的关系，进一步定义囊肿形成的细胞途径。我们建议鉴定额外的基因（例如，PLD 3）负责ADPLD。我们将使用小鼠模型来测试ADPLD中囊肿形成需要体细胞二次命中的假设，ADPKD中的情况也是如此。我们将确定Prkcsh和Sec 63突变是否导致Pkd 1、Pkd 2和Pkhd 1基因产物的不适当成熟和纤毛递送。这些研究将提高我们对多囊疾病的细胞和分子基础的理解，通过使用我们发现PRKCSH和SEC 63作为疾病基因而成为可能的致病途径的新切入点。与此同时，我们将提高我们对ADPLD作为一种疾病的理解，并发展有助于受这种疾病影响的患者的见解。

DESCRIPTION (provided by applicant): Our research program centers on achieving a comprehensive molecular understanding of human polycystic liver and kidney disease. Our goal is discovery novel paradigms for effective treatment of patients. We have taken an approach that begins with disease gene discovery through positional cloning to understand the genetic bases for the diseases, followed by functional studies to understand cellular pathogenesis. Under the current grant, we recruited patients with isolated autosomal dominant polycystic liver disease (ADPLD; MIM 174050) and completed a comprehensive clinical characterization of the disease. We established genetic linkage for one locus, PLD1, and discovered the disease gene, PRKCSH. We identified a second locus for ADPLD on chromosome 6 and identified human SEC63 as PLD2. Mutations in these genes account for ~ 25% of ADPLD probands in our cohort and suggest that there is at least one additional locus, PLD3, for ADPLD. PRKCSH encodes the B-subunit of glucosidase II (GIIB), a glucose trimming enzyme involved in protein maturation and quality control in the ER. SEC63 encodes a component of the ER protein translocation machinery that functions in concert with GII to achieve proper topology and folding of integral membrane or secreted glycoproteins. This proposal seeks to further define cellular pathways to cyst formation by discovery of additional genes involved in ADPLD, by determining whether two hits are required for cyst formation in ADPLD, and by defining the relationship between protein maturation in the ER and the normal function of primary cilia in bile duct epithelium. We propose to identify additional genes (e.g., PLD3) responsible for ADPLD by use of a combination of "classical" positional cloning and candidate gene approaches. We will use mouse models to test the hypothesis that cyst formation in ADPLD requires somatic second hits as is the case in ADPKD. We will determine whether Prkcsh and Sec63 mutations result in improper maturation and cilial delivery of the Pkd 1, Pkd2 and Pkhd 1 gene products. These studies will improve our understanding of the cellular and molecular bases of polycystic diseases by using the novel entry points into the pathogenic pathways made possible by our discovery of PRKCSH and SEC63 as disease genes. At the same time, we will improve our understanding of ADPLD as a disease condition and develop insights that will help patients affected by this condition.