Universität zu Köln

Riehle, Marc, Buescher, Anja K., Gohlke, Bjoern-Oliver, Kassmann, Mario, Kolatsi-Joannou, Maria, Braesen, Jan H., Nagel, Mato, Becker, Jan U., Winyard, Paul, Hoyer, Peter F., Preissner, Robert, Krautwurst, Dietmar, Gollasch, Maik, Weber, Stefanie and Harteneck, Christian (2016). TRPC6 G757D Loss-of-Function Mutation Associates with FSGS. J. Am. Soc. Nephrol., 27 (9). S. 2771 - 2784. WASHINGTON: AMER SOC NEPHROLOGY. ISSN 1533-3450

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Riehle, Marc UNSPECIFIED UNSPECIFIED UNSPECIFIED Buescher, Anja K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Gohlke, Bjoern-Oliver UNSPECIFIED UNSPECIFIED UNSPECIFIED Kassmann, Mario UNSPECIFIED UNSPECIFIED UNSPECIFIED Kolatsi-Joannou, Maria UNSPECIFIED UNSPECIFIED UNSPECIFIED Braesen, Jan H. UNSPECIFIED UNSPECIFIED UNSPECIFIED Nagel, Mato UNSPECIFIED UNSPECIFIED UNSPECIFIED Becker, Jan U. UNSPECIFIED UNSPECIFIED UNSPECIFIED Winyard, Paul UNSPECIFIED UNSPECIFIED UNSPECIFIED Hoyer, Peter F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Preissner, Robert UNSPECIFIED UNSPECIFIED UNSPECIFIED Krautwurst, Dietmar UNSPECIFIED UNSPECIFIED UNSPECIFIED Gollasch, Maik UNSPECIFIED UNSPECIFIED UNSPECIFIED Weber, Stefanie UNSPECIFIED UNSPECIFIED UNSPECIFIED Harteneck, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-265770
DOI:	10.1681/ASN.2015030318
Journal or Publication Title:	J. Am. Soc. Nephrol.
Volume:	27
Number:	9
Page Range:	S. 2771 - 2784
Date:	2016
Publisher:	AMER SOC NEPHROLOGY
Place of Publication:	WASHINGTON
ISSN:	1533-3450
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language FOCAL SEGMENTAL GLOMERULOSCLEROSIS; RESISTANT NEPHROTIC SYNDROME; CATION CHANNEL; MICROSCOPY REVEALS; ADULT PATIENTS; GENE VARIANTS; FORM; CHILDHOOD; CHILDREN; DISEASE Multiple languages Urology & Nephrology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/26577