ADPKD: Disease Spectrum & Genotype-Phenotype Correlations

Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited disorder that results in progressive renal insufficiency and often kidney failure and accounts for ~5% of US kidney transplant and dialysis patients. ADPKD is phenotypically and genetically heterogeneous with seven genes now associated with this disease, including the major loci, PKD1 and PKD2. Large patient populations collected at Mayo Clinic have been central to new gene identification, and newly available populations of normal individuals with whole exome sequencing and clinical data are providing insight into the penetrance of ADPKD genes and alleles. In Aim 1, using these populations we will determine the extent to which phenotypes within the ADPKD spectrum are dictated by novel genes, and explore the penetrance of known alleles. Allelic diversity and complexity, especially for PKD1, has made diagnostics for this disorder complex, with many patients not obtaining a definite genetic diagnosis following testing using the existing variant evaluation guidelines; only variants of uncertain significance (VUS) are defined. Functional, cellular assays and whole animal systems can help to determine pathogenicity and penetrance of variants classified as VUS. In Aim 2 we will employ cellular and in vivo studies to determine the mechanism(s) of disease causation for PKD1 and PKD2 pathogenic variants. These studies will improve diagnostics and generate models that together will unravel the pathogenic mechanism of many nontruncating variants and allow the associated disease to be modeled. Insights into the pathomechanism of disease can also highlight new treatment options that are proximal to the primary genetic defect, strategies that have been successful exploited for other monogenic disorders. Two variant types in particular, missense changes that result in folding and trafficking problems, and nonsense variants are common causes of disease in PKD1 and PKD2. In Aim 3 we will, explore allele-based treatment options for ADPKD. Specifically, chaperone treatments will be tested for missense variants where a folding/trafficking defect is the mutational mechanism, and the value of readthrough drugs for a variety of PKD1 and PKD2 nonsense variants will be tested, both with cellular assays and in vivo systems. Treatment options for ADPKD also depend on better understanding the mutational mechanism at the level of the cyst; there has long been controversy in ADPKD about the importance and timing of somatic second hits for cyst initiation and/or expansion. In Aim 4 we will investigate the role of somatic changes in cyst initiation and development using single cell DNA sequencing methods. Overall, our proposal will result in better understand the pathomechanisms associated with the genetic complexity of ADPKD, with the premise that improved understanding will result in new targeted therapeutic options.