Referenced in: none

Automatically associated channels: TRP , TRPC , TRPC6

Title: TRPC6 G757D Loss-of-Function Mutation Associates with FSGS.

Authors: Marc Riehle, Anja K Büscher, Björn-Oliver Gohlke, Mario Kassmann, Maria Kolatsi-Joannou, Jan H Bräsen, Mato Nagel, Jan U Becker, Paul Winyard, Peter F Hoyer, Robert Preissner, Dietmar Krautwurst, Maik Gollasch, Stefanie Weber, Christian Harteneck

Journal, date & volume: J. Am. Soc. Nephrol., 2016 Feb 18 , ,

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/26892346

Abstract
FSGS is a CKD with heavy proteinuria that eventually progresses to ESRD. Hereditary forms of FSGS have been linked to mutations in the transient receptor potential cation channel, subfamily C, member 6 (TRPC6) gene encoding a nonselective cation channel. Most of these TRPC6 mutations cause a gain-of-function phenotype, leading to calcium-triggered podocyte cell death, but the underlying molecular mechanisms are unclear. We studied the molecular effect of disease-related mutations using tridimensional in silico modeling of tetrameric TRPC6. Our results indicated that G757 is localized in a domain forming a TRPC6-TRPC6 interface and predicted that the amino acid exchange G757D causes local steric hindrance and disruption of the channel complex. Notably, functional characterization of model interface domain mutants suggested a loss-of-function phenotype. We then characterized 19 human FSGS-related TRPC6 mutations, the majority of which caused gain-of-function mutations. However, five mutations (N125S, L395A, G757D, L780P, and R895L) caused a loss-of-function phenotype. Coexpression of wild-type TRPC6 and TRPC6 G757D, mimicking heterozygosity observed in patients, revealed a dominant negative effect of TRPC6 G757D. Our comprehensive analysis of human disease-causing TRPC6 mutations reveals loss of TRPC6 function as an additional concept of hereditary FSGS and provides molecular insights into the mechanism responsible for the loss-of-function phenotype of TRPC6 G757D in humans.