A missense mutation in PKD1 attenuates the severity of renal disease

Mutations of PKD1 and PKD2 account for most cases of autosomal dominant polycystic kidney disease (ADPKD). Compared to PKD2, patients with PKD1 typically have more severe renal disease. Here, we report a follow-up study of a unique multi-generation family with bilineal ADPKD (NFL10) in which a PKD1 disease haplotype and a PKD2 (L736X) mutation co-segregated with 18 and 14 affected individuals, respectively. In our updated genotype-phenotype analysis of NFL10, we found that PKD1-affected individuals had uniformly mild renal disease similar to PKD2-affected individuals. By sequencing all the exons and splice junctions of PKD1, we identified two missense mutations (Y528C and R1942H) from a PKD1-affected individual. Although both variants were predicted to be damaging to the mutant protein, only Y528C co-segregated with all the PKD1-affected individuals in NFL10. To further establish the pathogenicity of Y528C, we performed in-vitro studies in stable MDCK cell lines expressing wild-type and mutant forms of PKD1. We found that MDCK cell lines expressing the Y528C variant formed cysts in culture and demonstrated increased rates of growth and apoptosis. Taken together, our data suggest that Y528C functions as a hypomorphic PKD1 allele. These findings have important implications for pathogenic mechanisms and molecular diagnostics of ADPKD.