Trans-ethnic characterization of the PKD2 founder variant p.Arg803* for investigating variable organ involvement in ADPKD

• Applicants: Professor Dr. Jan Halbritter; Dr. Michael Kaminski
• Subject Area: Nephrology ; Human Genetics
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 563665589

Autosomal-dominant polycystic kidney disease (ADPKD) is a common and systemic genetic disorder mainly caused by sequence alterations in either PKD1 or PKD2 and leading to kidney failure between the 4th and the 9th decade of life. In addition to variable renal survival, there is vast heterogeneity concerning the two most important extra-renal organ involvements: i) polycystic liver disease (PLD) and ii) intracranial aneurysms (ICA). While current genotype-phenotype correlations poorly explain disease variability, we aim to identify distinct genetic traits that can serve as early markers for renal and extra-renal disease severity and would allow for improved prognostication and potential interference. Recently, identification of the PKD2-founder variant p.Arg803* accounting for 18% (N=350) of all registered PKD2-patients in Taiwan, prompted us to successfully recruit affected carriers outside of Taiwan (N=140). As this unique situation of a larger ADPKD-study population with the identical primary diagnostic germline variant greatly facilitates identification of modifying germline factors, we collaborate with the National PKD Consortium in Taiwan. In detail, we propose the following three specific aims: i) Systematic assessment of the frequency of PKD2-p.Arg803* in cohorts beyond Taiwan focusing on European individuals with the goal of extending the overall study population for trans-ethnic comparison of predefined clinical kidney, liver, and brain (ICA) endpoints. ii) Determination of the presence of specific genetic (e.g. PRKCSH) and environmental (e.g. BMI) modifiers in affected carriers of PKD2-p.Arg803* in order to investigate modifier impact on clinical kidney, liver, and brain (ICA) endpoints. iii) Investigation of signaling alterations in cell lines and phenotypic and transcriptomic analysis of kidney organoids at single cell resolution. Organoids are derived from induced pluripotent stem cells carrying the PKD2-p.Arg803* founder variant and a PKD1-p.Ile3167Phe candidate modifier variant. Through successful implementation of these aims, we generate a valuable resource and contribute to overcome technical hurdles for systematic and holistic investigation of genetic and environmental factors in ADPKD.

• DFG Programme: Research Grants