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Dual Functional States of R406W-Desmin Assembly Complexes Cause Cardiomyopathy With Severe Intercalated Disc Derangement in Humans and in Knock-In Mice

Herrmann, H. and Cabet, E. and Chevalier, N.R. and Moosmann, J. and Schultheis, D. and Haas, J. and Schowalter, M. and Berwanger, C. and Weyerer, V. and Agaimy, A. and Meder, B. and Müller, O.J. and Katus, H.A. and Schlötzer-Schrehardt, U. and Vicart, P. and Ferreiro, A. and Dittrich, S. and Clemen, C.S. and Lilienbaum, A. and Schröder, R. (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), pp. 2155-2171. Lippincott, Williams & Wilkins. doi: 10.1161/CIRCULATIONAHA.120.050218. ISSN 0009-7322.

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Official URL: https://www.ahajournals.org/doi/10.1161/CIRCULATIONAHA.120.050218

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 URL in elib:https://elib.dlr.de/140138/
Document Type:Article
Title:Dual Functional States of R406W-Desmin Assembly Complexes Cause Cardiomyopathy With Severe Intercalated Disc Derangement in Humans and in Knock-In Mice
Authors:
AuthorsInstitution or Email of AuthorsAuthor's ORCID iD
Herrmann, H.Institute of Neuropathology, University Hospital ErlangenUNSPECIFIED
Cabet, E.Unit of Functional and Adaptive Biology (E.C., P.V., A.F., A.L.), University of Paris, France.UNSPECIFIED
Chevalier, N.R.Laboratoire Matière et Systèmes Complexes (N.R.C.), University of Paris, France.UNSPECIFIED
Moosmann, J.Department of Pediatric Cardiology (J.M., S.D.), University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, GermanyUNSPECIFIED
Schultheis, D.Institute of Neuropathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nu¨rnberg, Schwabachanlage, Erlangen, GermanyUNSPECIFIED
Haas, J.Institute for Cardiomyopathies Heidelberg, Heart Center Heidelberg, University of Heidelberg, GermanyUNSPECIFIED
Schowalter, M.Institute of Neuropathology, University Hospital Erlangen, FriedrichAlexander University Erlangen-Nurnberg, Erlangen, GermanyUNSPECIFIED
Berwanger, C.Muscle and Bone Metabolism Department, DLR, Institute of Aerospace Medicine, Cologne, GermanyUNSPECIFIED
Weyerer, V.Institute of Pathology (V.W., A.A.), University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, GermanyUNSPECIFIED
Agaimy, A.Institute of Pathology (V.W., A.A.), University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Germanyhttps://orcid.org/0000-0002-0445-8161
Meder, B.Institute for Cardiomyopathies Heidelberg, Heart Center Heidelberg, University of Heidelberg, Germanyhttps://orcid.org/0000-0003-0741-2633
Müller, O.J.Internal Medicine III, University Hospital Schleswig-Holstein and University of Kiel, and German Center for Cardiovascular Research, partner site Hamburg/Kiel/Lübeck, Kiel, GermanyUNSPECIFIED
Katus, H.A.Internal Medicine III, University Hospital Heidelberg, Heidelberg, GermanyUNSPECIFIED
Schlötzer-Schrehardt, U.Department of Opthalmology, University Hospital Erlangen, Friedrich-Alexander University ErlangenNu¨rnberg, Schwabachanlage, Erlangen, GermanyUNSPECIFIED
Vicart, P.Basic and Translational Myology, Unit of Functional and Adaptive Biology (E.C., P.V., A.F., A.L.), University of Paris, France.UNSPECIFIED
Ferreiro, A.Basic and Translational Myology, Unit of Functional and Adaptive Biology (E.C., P.V., A.F., A.L.), University of Paris, FranceUNSPECIFIED
Dittrich, S.Department of Pediatric Cardiology (J.M., S.D.), University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Germanyhttps://orcid.org/0000-0002-8455-3416
Clemen, C.S.Institute of Aerospace Medicine, German Aerospace Center (DLR), 51147 Cologne, Germanyhttps://orcid.org/0000-0002-1291-4219
Lilienbaum, A.Alain Lilienbaum, PhD, Basic and Translational Myology Laboratory, Unit of Functional and Adaptive Biology/CNRS UMR 8251, Université de Paris, 5 Rue Lagroua-Weill Hallé, 75013 Paris, FranceUNSPECIFIED
Schröder, R.Institute of Neuropathology, University Hospital Erlangen, Friedrich-Alexander University Erlangen-Nürnberg, Schwabachanlage, Erlangen, GermanyUNSPECIFIED
Date:7 October 2020
Journal or Publication Title:Circulation
Refereed publication:Yes
Open Access:No
Gold Open Access:No
In SCOPUS:Yes
In ISI Web of Science:Yes
Volume:142
DOI :10.1161/CIRCULATIONAHA.120.050218
Page Range:pp. 2155-2171
Publisher:Lippincott, Williams & Wilkins
ISSN:0009-7322
Status:Published
Keywords:cardiomyopathies, intermediate filaments, muscle, smooth desmosomes, muscle, striated Desmin, intestinal pseudo-obstruction
HGF - Research field:Aeronautics, Space and Transport
HGF - Program:Space
HGF - Program Themes:Research under Space Conditions
DLR - Research area:Raumfahrt
DLR - Program:R FR - Research under Space Conditions
DLR - Research theme (Project):R - Vorhaben Systemphysiologie (old)
Location: Köln-Porz
Institutes and Institutions:Institute of Aerospace Medicine > Muscle and Bone Metabolism
Deposited By: Arndt, Carina
Deposited On:11 Jan 2021 12:06
Last Modified:12 Jan 2021 13:29

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