Document text
Principal Investigator: Peter C. Harris
Organization: MAYO CLINIC ROCHESTER
Fiscal Year: 2024
Award: $675,412
Funding agency: National Institute of Diabetes and Digestive and Kidney Diseases
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.
Terms: <ADPKD><Accounting><Address><Adult Polycystic Kidney Disease><Alleles><Allelomorphs><Animal Model><Animal Models and Related Studies><Animals><Assay><Autosomal Dominant Polycystic Kidney><Autosomal Dominant Polycystic Kidney Disease><Bioassay><Biologic Models><Biological Assay><Biological Models><Causality><Cell Body><Cell Communication and Signaling><Cell Signaling><Cells><Cellular Assay><Chaperone><Cilia><Classification><Clinic><Clinical Data><Complex><Cyst><Cystic kidney><DNA seq><DNA sequencing><DNAseq><Data><Defect><Development><Diagnostic><Dialysis><Dialysis patients><Dialysis procedure><Disease><Disorder><Dominant Polycystic Kidney Disease><Drugs><Endopeptidase PC2><Etiology><Evaluation><Event><Evolution><FDA approved><Genes><Genetic><Genetic Alteration><Genetic Change><Genetic defect><Genotype><Goals><Grant><Guidelines><Hereditary Disease><In Vitro><Inborn Genetic Diseases><Individual><Inherited disorder><Intracellular Communication and Signaling><Kidney Cyst><Kidney Diseases><Kidney Failure><Kidney Grafting><Kidney Insufficiency><Kidney Transplantation><Kidney Transplants><Location><Measures><Medication><Mendelian disease><Mendelian disorder><Mendelian genetic disorder><Methods><Mice><Mice Mammals><Minor><Model System><Modeling><Molecular Chaperones><Murine><Mus><Mutation><NGS Method><NGS system><Nature><Nephropathy><Neuroendocrine Convertase PC1><Neuroendocrine Convertase PC2><PC1><PC1 Endoprotease><PC1 Prohormone Convertase><PC2><PC2 Endoprotease><PC2 Prohormone Convertase><PC2 Protein><PC3 Endoprotease><PC3 Prohormone Convertase><PKD1 protein><PKD2 protein><Pathogenesis><Pathogenicity><Patients><Penetrance><Pharmaceutical Preparations><Phenotype><Play><Population><Preclinical Testing><Prohormone Convertase 1><Prohormone Convertase 2><Prohormone Convertase 3><Proinsulin Convertase 1><Proinsulin Convertase 2><Proprotein Convertase 1><Proprotein Convertase 2><Proprotein Convertase SPC3><Protein Secretion><Protein Trafficking><Proteins><Renal Cyst><Renal Disease><Renal Failure><Renal Grafting><Renal Insufficiency><Renal Transplantation><Renal Transplants><Role><SEQ-AN><Sequence Analyses><Sequence Analysis><Signal Transduction><Signal Transduction Systems><Signaling><Single cell seq><Somatic Mutation><System><Systematics><Testing><Transplant Recipients><Variant><Variation><aberrant protein folding><abnormal protein folding><biological signal transduction><causation><cell assay><clinical diagnosis><developmental><dialysis therapy><disease causation><disease phenotype><dosage><drug/agent><exome sequencing><exome-seq><genetic diagnosis><genetic disorder diagnosis><genome mutation><hereditary disorder><heritable disorder><improved><in vitro testing><in vivo><in vivo Model><inborn error><inherited diseases><inherited genetic disease><inherited genetic disorder><insight><kidney disorder><kidney tx><membrane biogenesis><model of animal><monogenic disease><monogenic disorder><new drug target><new drug treatments><new druggable target><new drugs><new pharmacological therapeutic><new pharmacotherapy target><new therapeutic target><new therapeutics><new therapy><new therapy target><next gen sequencing><next generation sequencing><next generation therapeutics><nextgen sequencing><novel><novel drug target><novel drug treatments><novel druggable target><novel drugs><novel pharmaco-therapeutic><novel pharmacological therapeutic><novel pharmacotherapy target><novel therapeutic target><novel therapeutics><novel therapy><novel therapy target><pathogenicity gene><pathologic protein folding><patient population><pcy protein><polycystic breakpoint protein><polycystic kidney disease 1 protein><polycystic kidney disease 2 protein><polycystin 1><polycystin 2><pre-clinical testing><protein misfolding><protein transport><rare allele><rare mutation><rare variant><renal disorder><screening><screenings><side effect><single cell next generation sequencing><single cell sequencing><single-gene disease><single-gene disorder><social role><somatic variant><trafficking><transplant patient><treatment strategy><unclassified variant><variant of uncertain clinical significance><variant of uncertain significance><variant of undetermined significance><variant of unknown significance><virulence gene><virulent gene>