Desmin mutations as a cause of right ventricular heart failure affect the intercalated disks.

Abstract

BACKGROUND:

Mutations in the gene encoding desmin (DES), an intermediate filament protein, underlie a heterogeneous phenotype, which is referred to as desmin-related myopathy (DRM). Right ventricular involvement including an arrhythmogenic right ventricular cardiomyopathy (ARVC)(-like) phenotype has occasionally been described in DES mutation-carrying patients.

OBJECTIVE:

To determine the effects of a DES missense mutation on the structure of different intercalated disk proteins, to evaluate right ventricular involvement in DES mutation carriers, and to establish the role of DES mutations in ARVC(-like) phenotypes.

METHODS:

We evaluated the clinical phenotype in two families carrying two different DES mutations. One family was diagnosed with DRM, with an ARVC(-like) phenotype in one patient, while the other family presented with a severe biventricular cardiomyopathy. Additional immunohistochemistry of desmosomal proteins was performed in myocardial tissue from two patients of the last family. The DES gene was screened for mutations in 50 ARVC(-like) patients.

RESULTS:

Except for two different DES mutations (p.N342D and p.R454W) in two families with DRM and severe biventricular cardiomyopathy, respectively, we did not find additional DES mutations in ARVC(-like) patients. In addition to desmin aggregates, immunohistochemistry demonstrated a decreased amount of desmoplakin and plakophilin-2 at the intercalated disk in p.R454W mutation carriers.

CONCLUSIONS:

We confirmed that either an ARVC-like phenotype or a severe cardiomyopathy with right ventricular involvement are possible, yet infrequent, cardiac phenotypes in DRM. Moreover, we demonstrated that the DES mutation p.R454W affects the localization of desmoplakin and plakophilin-2 at the intercalated disk, suggesting a link between desmosomal cardiomyopathies (mainly affecting the right ventricle) and cardiomyopathies caused by DES mutations.

• Authors: Ellen Otten, Angeliki Asimaki, Alexander Maass, Irene M van Langen, Allard van der Wal, Nicolaas de Jonge, Maarten P van den Berg, Jeffrey E Saffitz, Arthur A M Wilde, Jan D H Jongbloed, J Peter van Tintelen
• Journal: Heart rhythm (Heart Rhythm) Vol. 7 Issue 8 Pg. 1058-64 (Aug 2010) ISSN: 1556-3871 [Electronic] United States
• PMID: 20423733 (Publication Type: Journal Article)
• Copyright: Copyright 2010 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Chemical References

• Desmin

Topics

• Adult
• Arrhythmogenic Right Ventricular Dysplasia (complications, genetics)
• Cardiomyopathies (complications, genetics)
• Child
• Desmin (genetics)
• Female
• Heart Failure (etiology, genetics)
• Heart Ventricles
• Heterozygote
• Humans
• Intercellular Junctions (physiology)
• Male
• Mutation, Missense
• Pedigree
• Phenotype