A mutation affecting polycystin-1 mediated heterotrimeric G-protein signaling causes PKD. Hum Mol Genet 2018 Oct 01;27(19):3313-3324
Date
06/23/2018Pubmed ID
29931260Pubmed Central ID
PMC6140781DOI
10.1093/hmg/ddy223Scopus ID
2-s2.0-85059535934 (requires institutional sign-in at Scopus site) 31 CitationsAbstract
Autosomal dominant polycystic kidney disease (ADPKD) is characterized by the growth of renal cysts that ultimately destroy kidney function. Mutations in the PKD1 and PKD2 genes cause ADPKD. Their protein products, polycystin-1 (PC1) and polycystin-2 (PC2) have been proposed to form a calcium-permeable receptor-channel complex; however the mechanisms by which they function are almost completely unknown. Most mutations in PKD1 are truncating loss-of-function mutations or affect protein biogenesis, trafficking or stability and reveal very little about the intrinsic biochemical properties or cellular functions of PC1. An ADPKD patient mutation (L4132Δ or ΔL), resulting in a single amino acid deletion in a putative G-protein binding region of the PC1 C-terminal cytosolic tail, was found to significantly decrease PC1-stimulated, G-protein-dependent signaling in transient transfection assays. Pkd1ΔL/ΔL mice were embryo-lethal suggesting that ΔL is a functionally null mutation. Kidney-specific Pkd1ΔL/cond mice were born but developed severe, postnatal cystic disease. PC1ΔL protein expression levels and maturation were comparable to those of wild type PC1, and PC1ΔL protein showed cell surface localization. Expression of PC1ΔL and PC2 complexes in transfected CHO cells failed to support PC2 channel activity, suggesting that the role of PC1 is to activate G-protein signaling to regulate the PC1/PC2 calcium channel.
Author List
Parnell SC, Magenheimer BS, Maser RL, Pavlov TS, Havens MA, Hastings ML, Jackson SF, Ward CJ, Peterson KR, Staruschenko A, Calvet JPMESH terms used to index this publication - Major topics in bold
AnimalsCHO Cells
Calcium Channels
Cilia
Cricetulus
Heterotrimeric GTP-Binding Proteins
Humans
Kidney
Mice
Mutation
Polycystic Kidney, Autosomal Dominant
Protein Domains
Signal Transduction
TRPP Cation Channels
