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J Am Soc Nephrol. 2009 Jun;20(6):1188-98. doi: 10.1681/ASN.2009010014. Epub 2009 May 7.

2008 Homer W. Smith Award: insights into the pathogenesis of polycystic kidney disease from gene discovery.

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  • 1Division of Nephrology and Hypertension, Mayo Clinic Rochester, 200 First Street SW, Rochester, MN 55905, USA.


Polycystic kidney diseases (PKD) are a group of inherited disorders characterized by morbidity-associated development of renal cysts. Three forms of PKD are described here: The common, late onset, autosomal dominant PKD (ADPKD); the mainly infantile, autosomal recessive PKD (ARPKD); and the lethal, syndromic, Meckel syndrome that also includes central nervous system and digital defects. Positional cloning approaches based on genetic linkage have identified the disease genes in these disorders. Completion of the Human Genome Project, cases with atypical mutation, and animal models have greatly aided gene identification, and characterization of the disease genes has allowed establishment of molecular diagnostics. Genetic and allelic heterogeneity, plus genetic modification, underlie the significant phenotypic variability in each disorder. Positional cloning identified novel disease-associated protein families: The polycystins (ADPKD); fibrocystins (ARPKD); and meckelin. A common feature of pathogenesis in each disorder seems to be the primary cilia, implicating detection of fluid flow and the developmental process of planar cell polarity. Identifying the primary defect has contributed to our understanding of defective cellular processes and highlights potential therapeutic targets. A number of agents are now in Phase 3 trials, and many others show promise preclinically, providing hope of effective treatments for ADPKD in the foreseeable future.

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