Autosomal dominant polycystic liver disease without kidney cysts (ADPLD) is a genetically distinct, heritable disease characterized by the presence of multiple, scattered cysts in the liver parenchyma not associated with cyst formation in the kidney. We have performed a genome-wide scan for linkage using several ADPLD families and identified a major locus for the disease confined to a ~10 centiMorgan interval on human chromosome 19p13.2. The overall goals of our program for studying polycystic liver disease (PLD) are (1) phenotypic characterization of individuals with PLD and families with ADPLD, (2) identification of the gene (PLD1) mutated in human ADPLD, (3) elucidation of the mechanisms by which mutations result in the observed phenotype, (4) discovery of the factors that modify the expression of the ADPLD phenotype, (5) understanding the role of PLD1 in human cystic diseases in general, and (6) discovery of approaches for modulating the phenotypic effects of mutations in PLD1. The present proposal focuses on the characterization of the ADPLD phenotype and the identification of responsible human disease gene by positional cloning. We propose to undertake a comprehensive characterization of the clinical phenotype of ADPLD to determine whether patients with ADPLD have extrarenal manifestations that overlap with those of patients with autosomal dominant polycystic kidney disease (ADPKD) and establish whether the severity of the liver cystic disease in ADPLD correlates with the same factors known to influence the severity of the liver cystic disease in ADPKD. We plan to establish whether most patients with a presentation of polycystic liver disease (PLD) without renal involvement have familial ADPLD. We will use positional cloning to identify PLD1. Positional cloning will require refinement of the recombinatorial boundaries of the ADPLD genetic interval by definition of """"""""critical recombinants"""""""" and construction of a detailed physical map of the interval. This physical map will be used to isolate all expressed sequences from the refined ADPLD candidate region. Candidate genes will be scanned to identify disease related mutations. Once identified, we will characterize the nature of the ADPLD mutations, study the genomic organization of the PLD1 gene, and determine if there is a relationship between genotype and phenotype in ADPLD.
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