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TRPC6 G757D loss-of-function mutation associates with FSGS

Item Type:Article
Title:TRPC6 G757D loss-of-function mutation associates with FSGS
Creators Name:Riehle, M. and Büscher, A.K. and Gohlke, B.O. and Kaßmann, M. and Kolatsi-Joannou, M. and Bräsen, J.H. and Nagel, M. and Becker, J.U. and Winyard, P. and Hoyer, P.F. and Preissner, R. and Krautwurst, D. and Gollasch, M. and Weber, S. and Harteneck, C.
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.
Keywords:Glomerular Disease, Glomerulosclerosis, Ion Channel, Calcium, Kidney Disease
Source:Journal of the American Society of Nephrology
Publisher:American Society of Nephrology
Page Range:2771-2783
Date:September 2016
Official Publication:https://doi.org/10.1681/ASN.2015030318
PubMed:View item in PubMed

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