Universität zu Köln

Herrmann, Harald, Cabet, Eva, Chevalier, Nicolas R., Moosmann, Julia, Schultheis, Dorothea, Haas, Jan, Schowalter, Mirjam, Berwanger, Carolin, Weyerer, Veronika, Agaimy, Abbas, Meder, Benjamin, Muller, Oliver J., Katus, Hugo A., Schlotzer-Schrehardt, Ursula, Vicart, Patrick, Ferreiro, Ana, Dittrich, Sven, Clemen, Christoph S., Lilienbaum, Alain and Schroeder, Rolf (2020). Dual Functional States of R406W-Desmin Assembly Complexes Cause Cardiomyopathy With Severe Intercalated Disc Derangement in Humans and in Knock-In Mice. Circulation, 142 (22). S. 2155 - 2172. PHILADELPHIA: LIPPINCOTT WILLIAMS & WILKINS. ISSN 1524-4539

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Abstract

Background: Mutations in the human desmin gene cause myopathies and cardiomyopathies. This study aimed to elucidate molecular mechanisms initiated by the heterozygous R406W-desmin mutation in the development of a severe and early-onset cardiac phenotype. Methods: We report an adolescent patient who underwent cardiac transplantation as a result of restrictive cardiomyopathy caused by a heterozygous R406W-desmin mutation. Sections of the explanted heart were analyzed with antibodies specific to 406W-desmin and to intercalated disc proteins. Effects of the R406W mutation on the molecular properties of desmin were addressed by cell transfection and in vitro assembly experiments. To prove the genuine deleterious effect of the mutation on heart tissue, we further generated and analyzed R405W-desmin knock-in mice harboring the orthologous form of the human R406W-desmin. Results: Microscopic analysis of the explanted heart revealed desmin aggregates and the absence of desmin filaments at intercalated discs. Structural changes within intercalated discs were revealed by the abnormal organization of desmoplakin, plectin, N-cadherin, and connexin-43. Next-generation sequencing confirmed the DES variant c.1216C>T (p.R406W) as the sole disease-causing mutation. Cell transfection studies disclosed a dual behavior of R406W-desmin with both its integration into the endogenous intermediate filament system and segregation into protein aggregates. In vitro, R406W-desmin formed unusually thick filaments that organized into complex filament aggregates and fibrillar sheets. In contrast, assembly of equimolar mixtures of mutant and wild-type desmin generated chimeric filaments of seemingly normal morphology but with occasional prominent irregularities. Heterozygous and homozygous R405W-desmin knock-in mice develop both a myopathy and a cardiomyopathy. In particular, the main histopathologic results from the patient are recapitulated in the hearts from R405W-desmin knock-in mice of both genotypes. Moreover, whereas heterozygous knock-in mice have a normal life span, homozygous animals die at 3 months of age because of a smooth muscle-related gastrointestinal phenotype. Conclusions: We demonstrate that R406W-desmin provokes its severe cardiotoxic potential by a novel pathomechanism, where the concurrent dual functional states of mutant desmin assembly complexes underlie the uncoupling of desmin filaments from intercalated discs and their structural disorganization.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Herrmann, Harald UNSPECIFIED UNSPECIFIED UNSPECIFIED Cabet, Eva UNSPECIFIED UNSPECIFIED UNSPECIFIED Chevalier, Nicolas R. UNSPECIFIED UNSPECIFIED UNSPECIFIED Moosmann, Julia UNSPECIFIED UNSPECIFIED UNSPECIFIED Schultheis, Dorothea UNSPECIFIED UNSPECIFIED UNSPECIFIED Haas, Jan UNSPECIFIED UNSPECIFIED UNSPECIFIED Schowalter, Mirjam UNSPECIFIED UNSPECIFIED UNSPECIFIED Berwanger, Carolin UNSPECIFIED UNSPECIFIED UNSPECIFIED Weyerer, Veronika UNSPECIFIED UNSPECIFIED UNSPECIFIED Agaimy, Abbas UNSPECIFIED UNSPECIFIED UNSPECIFIED Meder, Benjamin UNSPECIFIED UNSPECIFIED UNSPECIFIED Muller, Oliver J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Katus, Hugo A. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schlotzer-Schrehardt, Ursula UNSPECIFIED UNSPECIFIED UNSPECIFIED Vicart, Patrick UNSPECIFIED UNSPECIFIED UNSPECIFIED Ferreiro, Ana UNSPECIFIED UNSPECIFIED UNSPECIFIED Dittrich, Sven UNSPECIFIED UNSPECIFIED UNSPECIFIED Clemen, Christoph S. UNSPECIFIED UNSPECIFIED UNSPECIFIED Lilienbaum, Alain UNSPECIFIED UNSPECIFIED UNSPECIFIED Schroeder, Rolf UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-310243
DOI:	10.1161/CIRCULATIONAHA.120.050218
Journal or Publication Title:	Circulation
Volume:	142
Number:	22
Page Range:	S. 2155 - 2172
Date:	2020
Publisher:	LIPPINCOTT WILLIAMS & WILKINS
Place of Publication:	PHILADELPHIA
ISSN:	1524-4539
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language INTERMEDIATE-FILAMENTS; SKELETAL MYOPATHY; RESTRICTIVE CARDIOMYOPATHY; ATRIOVENTRICULAR-BLOCK; MUSCULAR-DYSTROPHY; MISSENSE MUTATIONS; DESMIN MUTATION; CULTURED-CELLS; VIMENTIN; EXPRESSION Multiple languages Cardiac & Cardiovascular Systems; Peripheral Vascular Disease Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/31024