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

Heart Rhythm. 2010 Aug;7(8):1058-64. doi: 10.1016/j.hrthm.2010.04.023. Epub 2010 Apr 24.

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.

MeSH terms

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

Substances

  • Desmin