ADPKD: Disease Spectrum &Genotype-Phenotype Correlations

Project: Research project

Project Details


DESCRIPTION (provided by applicant): Autosomal dominant polycystic kidney disease (ADPKD) is characterized by marked phenotypic variability both in terms of the severity of renal disease and extra-renal manifestations. Understanding why the disease presents and progresses differently in different individuals and families is of diagnostic, prognostic and mechanistic importance, and will help to direct future approaches to therapy. Genetic heterogeneity, involvement of the PKD1 or PKD2 gene, is known to significantly influence the severity of renal disease but the importance to other disease phenotypes is less clear. Improved mutation screening developed during the previous funding period has allowed allelic effects to be assayed. Mutation position in PKD1 was found to have a modest, but significant, influence on disease severity and to be a strong indicator of the propensity to develop vascular complications; 5' mutations associated with more serious disease. Studies of intrafamilial variability have also shown that genetic modifiers have a significant impact on the disease phenotype. We propose here to further improve mutation screening by the involvement of more direct sequencing. This mutation characterized ADPKD population will be used to better estimate the relative importance of genie, allelic and modifier effects on the disease phenotype. Linkage studies and mutation negative patients have suggested further genetic heterogeneity. Here, the validity, and identity, of a third ADPKD gene will be tested and sought by positional/candidate approaches. The role that gene type and PKD1 allelic effects have on the extremes of renal disease and polycystic liver disease (PLD), will be tested. A new association with idiopathic dilated cardiomyopathy (IDCM) will be clarified at the clinical and molecular level. Association studies will test the role that specific genetic modifiers have to influence the severity of renal disease, and of PLD. Finally, the mechanisms by which different PKD1 mutations may exert varied phenotypic effects will be assayed in cell-lines and whole animals with truncating mutations giving rise to stable polycystin-1 mutant products. The expression, localization and complexing functions of these aberrant molecules will be assayed by western blotting, immunofluorescence and immunoprecipitation to judge possible dominant negative mechanisms of mutation. [unreadable]
Effective start/end date12/1/005/31/18


  • Medicine(all)