The diverse effects of pathogenic point mutations on ion channel activity of a gain-of-function polycystin-2

Autosomal dominant polycystic kidney disease is caused by mutations in PKD1 or PKD2 genes. The latter encodes polycystin-2 (PC2, also known as TRPP2), a member of the transient receptor potential ion channel family. Despite most pathogenic mutations in PKD2 being truncation variants, there are also many point mutations, which cause small changes in protein sequences but dramatic changes in the in vivo function of PC2. How these mutations affect PC2 ion channel function is largely unknown. In this study, we systematically tested the ef-fects of 31 point mutations on the ion channel activity of a gain -of-function PC2 mutant, PC2_F604P, expressed in Xenopus oo-cytes. The results show that all mutations in the transmembrane domains and channel pore region, and most mutations in the extracellular tetragonal opening for polycystins domain, are critical for PC2_F604P channel function. In contrast, the other mutations in the tetragonal opening for polycystins domain and most mutations in the C-terminal tail cause mild or no effects on channel function as assessed in Xenopus oocytes. To understand the mechanism of these effects, we have discussed possible conformational consequences of these mutations based on the cryo-EM structures of PC2. The results help gain insight into the structure and function of the PC2 ion channel and the molecular mechanism of pathogenesis caused by these mutations.

Automated summary

Autosomal dominant polycystic kidney disease is caused by mutations in PKD1 or PKD2 genes, and this study investigated the effects of 31 point mutations on the ion channel activity of a PC2 mutant expressed in Xenopus oocytes. The results showed that mutations in the transmembrane domains, channel pore region, and extracellular tetragonal opening for polycystins domain were critical for PC2 channel function, while mutations in the tetragonal opening for polycystins domain and C-terminal tail had mild or no effects. The study provided insights into the structure and function of the PC2 ion channel and the molecular mechanism of pathogenesis caused by these mutations.