# Molecular pathology and cystogenic propensity of the ADPKD Taiwan founder variant

## TL;DR

This study examines how two PKD2 gene mutations cause different levels of kidney disease severity by affecting protein function and cilia localization.

## Contribution

The study reveals how variant-specific PKD2 dysfunction correlates with ADPKD severity and introduces new animal models for therapeutic testing.

## Key findings

- The R654X variant prevents channel assembly and ciliary trafficking, while R803X retains partial function.
- Mice with the R803X mutation showed slower cyst progression, mirroring milder patient outcomes.
- Cyst severity correlates with the degree of PKD2 trafficking impairment to primary cilia.

## Abstract

Renal polycystins (PKD1, PKD2) are ion channel–forming subunits that traffic to principal cell primary cilia. Variants in these proteins cause approximately 95% of autosomal dominant polycystic kidney disease (ADPKD), a common, lethal genetic disorder that lacks effective drug treatments. We assessed the mechanistic impact and pathogenic propensity of 2 disease-associated PKD2 truncating variants, R803X and R654X. Worldwide, hundreds of individuals with ADPKD harbor these germline mutations, including the R803X founder variant first identified within the patient population of Taiwan. Our biochemical, electrophysiological, and super-resolution imaging analyses demonstrated that the pore-truncating R654X variant abolished channel assembly and ciliary trafficking, whereas the R803X variant retained partial cilia trafficking and channel function. To assess disease impact, we generated transgenic mice with analogous truncation mutations. Homozygous mutants were embryonic lethal, whereas heterozygous mice expressing both variant and conditional Pkd2 repression alleles developed pronounced renal cysts. Cyst progression was slower in mice carrying the equivalent Taiwan mutation, reflecting the milder clinical course observed in patients. These findings revealed that the degree of impaired PKD2 channel trafficking to primary cilia correlated with cystic disease severity, providing insight into variant-specific ADPKD pathogenesis and newly developed animal models expressing clinically relevant variants for therapeutic testing.

Hundreds ADPKD patients harbor PKD2 gene truncating mutations, such as the Tawain founder variant, which confer variable cystogenic propensity driven by differences in molecular dysfunction and primary cilia localization.