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Desmosomal dysfunction due to mutations in desmoplakin causes arrhythmogenic right ventricular

Zhao Yang1, Neil E Bowles, Steven E Scherer

  • 1Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA.

Circulation Research
|August 19, 2006
PubMed

Insights

Desmoplakin (DSP) mutations cause arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) by disrupting cardiac integrity, leading to cell death and developmental defects. This study elucidates DSP

Area of Science:

  • Cardiovascular Genetics
  • Molecular Cardiology
  • Cell Biology

Background:

  • Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a genetic heart condition characterized by ventricular arrhythmias and sudden cardiac death.
  • Mutations in desmosomal proteins, including Desmoplakin (DSP), are implicated in ARVD/C pathogenesis.
  • Understanding the functional impact of DSP mutations is crucial for elucidating ARVD/C mechanisms.

Purpose of the Study:

  • To investigate the functional consequences of specific Desmoplakin (DSP) missense mutations (V30M, Q90R, R2834H) associated with ARVD/C.
  • To establish a causal link between DSP variants and the development of ARVD/C.
  • To explore the role of DSP in maintaining cardiac tissue integrity and function.

Main Methods:

  • In vitro studies using desmosome-forming cell lines to assess protein localization and interaction.
  • In vivo studies involving the generation of cardiac-specific transgenic mouse models overexpressing wild-type or mutant DSP.
  • Histological, morphological, and functional analyses of hearts from transgenic mice and embryonic studies.

Main Results:

  • N-terminal DSP mutants (V30M, Q90R) failed to localize to the cell membrane and bind to JUP, with cardiac-specific transgenes proving lethal during embryonic development.
  • C-terminal DSP mutant (R2834H) transgenic mice exhibited cardiomyocyte apoptosis, cardiac fibrosis, lipid accumulation, ventricular enlargement, and cardiac dysfunction.
  • Ultrastructural analysis revealed disrupted DSP-desmin interactions and significant changes in intercalated discs in R2834H mutant mice.

Conclusions:

  • DSP is essential for maintaining cardiomyocyte integrity and normal cardiac development.
  • DSP mutations lead to ARVD/C through mechanisms involving cardiomyocyte death, altered lipid metabolism, and impaired cardiac development.
  • DSP abnormalities at intercalated discs contribute significantly to the pathogenesis of ARVD/C.

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