TRPC6 G757D loss-of-function mutation associates with FSGS

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Item Type:	Article
Title:	TRPC6 G757D loss-of-function mutation associates with FSGS
Creators Name:	Riehle, M., Büscher, A.K., Gohlke, B.O., Kaßmann, M., Kolatsi-Joannou, M., Bräsen, J.H., Nagel, M., Becker, J.U., Winyard, P., Hoyer, P.F., Preissner, R., Krautwurst, D., Gollasch, M., 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
ISSN:	1046-6673
Publisher:	American Society of Nephrology
Volume:	27
Number:	9
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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