Class of ..., Class of 2023

No cyst is alike – studying a distinct PKD2-founder variant for better explaining disease variability


Carolin B. Brigl

Prinicipal Investigator

Prof. Dr. Jan Halbritter
Dr. Ria Schönauer

Scientific interest within the context of the graduate college:

Not Everything Is “Genetic”, but Genes Are Involved in Everything (adapted from Kenneth M. Weiss).

Our group is interested in the identification and investigation of genetic, clinical, and environmental factors determining the onset of chronic kidney disease (CKD) and kidney survival. We make use of next-generation sequencing techniques and deep-phenotyping to identify genetic variants that are predictive for disease progression or convey protection from organ failure. We functionally evaluate identified germline variants in vitro in order to understand underlying molecular mechanisms leading to CKD on the one hand or protecting from kidney failure on the other. By doing so, we aim at defining and targeting molecular switches responsible for health maintenance and disease alleviation.

Project description:

Introduction: One of six patients undergoing renal transplantation has autosomal-dominant polycystic kidney disease (ADPKD) caused by heterozygous germline mutations in one of two main disease genes, namely PKD1 or PKD2. ADPKD is the commonest genetic disorder leading to CKD including kidney failure (KF), cystic liver disease, and CNS-involvement in terms of intracranial aneurysms.1-3 KF from ADPKD commonly occurs between ages 30-80 years. While PKD1-associated disease is generally more severe than PKD2-disease, exemplified by a 20-year difference in mean age at KF (55 versus 75 years), current genotype-phenotype correlations only explain part of the observed disease variability.2,3 For example, some patients with even identical PKD2-mutations vary dramatically in their progression. We demonstrated that additional non-diagnostic hypomorphic PKD1/2-germline variants as well as variants in PKD-interactors mechanistically add to the mutational effect.3,4 Recently, collaborators of ours identified a single PKD2-mutation that collectively accounts for about 18% of all PKD2-cases in Taiwan (n=200): c.2407C>T, p.Arg803*.5 By a first genetic screening, we also found this variant in several families in Germany and France (n=30). This situation is unique in the field and strongly facilitates studying disease variability, as joint cohorts with the same diagnostic PKD-variant allow for completely new approaches to explain why some individuals experience kidney failure in mid-life and others seem to be protected. We aim to learn from families harboring this distinct PKD2 variant in Asia and Europe for transethnic comparison, proposing the following two specific aims:

Aim 1 / WP1: Identification and characterization of additional European cases with PKD2-Arg803*

While we have access to genetic and clinical data from the Taiwan cohort, we aim to further extend the European counterpart for transethnic comparison. Therefore, we will use platforms of the European Rare Kidney Disease Network (ERKNet)6 and the European Renal Association (ERA)7 to run online surveys across centers in whole Europe. We estimate to identify at least another 30-50 individuals with the PKD2-Arg803* variant for complete clinical characterization of kidney-, liver-, and CNS-involvement. Additionally, we also aim to capture environmental factors by sending out patient questionnaires. Lastly, we will run exome sequencing in all individuals available (n=60-80) for identification of additional germline variants likely accounting for disease progression versus disease protection.

Aim 2 / WP2: Functional studies with PKD2-Arg803* and comparison with other PKD-disease variants Characterization of urinary renal epithelial cells from individuals with PKD2-p.Arg803*. Overexpression of PKD2-Arg803* in established cell-culture models and consecutive comparison to established PKD2 gene variants. Consecutive use of established cellular read-outs on RNA and protein level. Planned analyses include qRT-PCR, Western Blot, and immunofluorescence imaging.


  1. Lanktree MB, Haghighi A, Guiard E, […], Harris PC, Paterson AD, Pei Y. Prevalence Estimates of Polycystic Kidney and Liver Disease by Population Sequencing. J Am Soc Nephrol. 2018; 29:2593-2600. doi: 10.1681/ASN.2018050493.
  2. Cornec-Le Gall E, Alam A, Perrone RD. Autosomal dominant polycystic kidney disease. Lancet. 2019; 393:919-935. doi: 10.1016/S0140-6736(18)32782-X.
  3. Schönauer R, Baatz S, Nemitz-Kliemchen M, […], Neuber S, Bergmann C, Halbritter J. Matching clinical and genetic diagnoses in autosomal dominant polycystic kidney disease reveals novel phenocopies and potential candidate genes. Genet Med. 2020; 22:1374-1383. doi: 10.1038/s41436-020-0816-3.
  4. Durkie, M. et al. Biallelic inheritance of hypomorphic PKD1 variants is highly prevalent in very early onset polycystic kidney disease. Genet Med. 2021; 23:689-697. doi: 10.1038/s41436-020-01026-4.
  5. Yu CC, Lee AF, Kohl S, […], Hildebrandt F; Taiwan PKD Consortium; Hwang DY. PKD2 founder mutation is the most common mutation of polycystic kidney disease in Taiwan. NPJ Genom Med. 2022; 7:40. doi: 10.1038/s41525-022-00309-w.