Autosomal dominant polycystic kidney disease (ADPKD) is one of the most common monogenic disorders (1:400-1000) and an important cause of end stage renal disease (ESRD). In the US in 2012, ~30,000 patients had PKD associated ESRD;1/3500 individuals aged 65-69y. The disease is generally late in onset, but considerable variability exists, from in utero onset and perinatal death, early onset (EO) disease, to adequate renal function into old age. Extrarenal manifestations, particularly a higher incidence of intracranial aneurysms (ICA) and severe polycystic liver disease (sPLD) are associated with morbidity and mortality. The overall goal of this proposal is to determine the extent to which genetic factors at the two known genes, PKD1 (16p13.3) and PKD2 (4q21) and elsewhere in the genome, determine the severity of renal disease and the occurrence of clinically significant extrarenal complications. These studies are based upon our findings, and those of others that genic, allelic and genetic background effects significantly influence the phenotype. Next generation sequencing (NGS) will be employed for mutation screening of the ADPKD genes, including the duplicated PKD1, necessitating enrichment by locus specific long-range PCR (LR-PCR). Mutations and variants elsewhere in the genome will be identified employing custom-made panels of candidate genes (HaloPlex methodology) and whole exome sequencing (WES).
Aim 1 will screen the ADPKD genes to identify atypical mutations in the 7-10% of patients that are presently unresolved, and assess the role of allelic combinations as pathogenic events, especially causing EO disease.
Aim 2 will analyze a large, typical ADPKD population and ones with the vascular and sPLD phenotype to determine the full role that ADPKD genic and allelic effects play in accounting for phenotypic variability.
Aim 3 will screen loci beyond the ADPKD genes, including the whole exome, for novel causative genes resulting in an ADPKD-like phenotype.
Aim 4 will analyze the whole exome for modifying factors that cause EO disease and clinically significant vascular and hepatic complications.
The final aim will test the significance of putative pathogenic ADPKD alleles in vivo, analyzing the mechanisms of pathogenesis and optimizing mouse models for preclinical testing. Overall these studies will better explain the genetic causes of ADPKD, provide insights into the pathogenesis, possibly revealing novel therapeutic targets, optimize models for preclinical testing, be of diagnostic and prognostic value, and identify populations suitable for clinical trials and that will gain most fro disease-specific therapeutics which will be available soon.

Public Health Relevance

Autosomal dominant polycystic kidney disease (ADPKD) is a common inherited kidney disease in which the majority of affected individuals develop renal failure, requiring dialysis or renal transplant during their adult life. Many different mutations t two different genes are known to cause the disease and have correlations between mutations and the severity and presentations of the disease in the patient population. Genetic variants in other genes will also be sought as novel causes of ADPKD or modifiers of the disease course. These studies will help understand the causes of the disease, suggesting new treatments, be of diagnostic and prognostic value, and identify a population that will gain most from treatment.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK058816-14
Application #
8755037
Study Section
Special Emphasis Panel (ZRG1-DKUS-N (04))
Program Officer
Rasooly, Rebekah S
Project Start
2000-12-01
Project End
2018-05-31
Budget Start
2014-09-08
Budget End
2015-05-31
Support Year
14
Fiscal Year
2014
Total Cost
$402,569
Indirect Cost
$149,381
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Paul, Binu M; Consugar, Mark B; Ryan Lee, Moonnoh et al. (2014) Evidence of a third ADPKD locus is not supported by re-analysis of designated PKD3 families. Kidney Int 85:383-92
Torres, Vicente E; Harris, Peter C (2014) Strategies targeting cAMP signaling in the treatment of polycystic kidney disease. J Am Soc Nephrol 25:18-32
Harris, Peter C; Torres, Vicente E (2014) Genetic mechanisms and signaling pathways in autosomal dominant polycystic kidney disease. J Clin Invest 124:2315-24
Vazifehmand, Reza; Rossetti, Sandro; Saber, Sassan et al. (2013) Molecular analysis of a consanguineous Iranian polycystic kidney disease family identifies a PKD2 mutation that aids diagnostics. BMC Nephrol 14:190
Paavola, Jere; Schliffke, Simon; Rossetti, Sandro et al. (2013) Polycystin-2 mutations lead to impaired calcium cycling in the heart and predispose to dilated cardiomyopathy. J Mol Cell Cardiol 58:199-208
Rossetti, Sandro; Harris, Peter C (2013) The genetics of vascular complications in autosomal dominant polycystic kidney disease (ADPKD). Curr Hypertens Rev 9:37-43
Harris, Peter C; Hopp, Katharina (2013) The mutation, a key determinant of phenotype in ADPKD. J Am Soc Nephrol 24:868-70
Herbert, Brittney-Shea; Grimes, Brenda R; Xu, Wei Min et al. (2013) A telomerase immortalized human proximal tubule cell line with a truncation mutation (Q4004X) in polycystin-1. PLoS One 8:e55191
Rossetti, Sandro; Hopp, Katharina; Sikkink, Robert A et al. (2012) Identification of gene mutations in autosomal dominant polycystic kidney disease through targeted resequencing. J Am Soc Nephrol 23:915-33
Mohney, Brian G; Pulido, Jose S; Lindor, Noralane M et al. (2011) A novel mutation of LAMB2 in a multigenerational mennonite family reveals a new phenotypic variant of Pierson syndrome. Ophthalmology 118:1137-44

Showing the most recent 10 out of 30 publications