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De novo desmin-mutation N116S is associated with arrhythmogenic right ventricular cardiomyopathy

Baerbel Klauke1, Sabine Kossmann, Anna Gaertner

  • 1Herz- & Diabeteszentrum NRW, Klinik f. Thorax- und Kardiovaskularchirurgie, Erich und Hanna Klessmann-Institutfür Kardiovaskulaere Forschung und Entwicklung/Klinik fuer angeborene Herzfehler, Georgstrasse 11, Bad Oeynhausen, Germany.

Human Molecular Genetics
|September 11, 2010
PubMed

Insights

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart condition. Genetic screening identified a novel desmin mutation linked to ARVC and heart failure, suggesting desmin as a new ARVC gene.

Area of Science:

  • Cardiology
  • Genetics
  • Molecular Biology

Background:

  • Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited heart muscle disease.
  • ARVC is a frequent cause of sudden cardiac death and terminal heart failure.
  • Genetic screening of ARVC patients aids in family palliative treatment.

Purpose of the Study:

  • To investigate mutations in desmosomal candidate genes (JUP, DSG2, DSC2, DSP, PKP2) in ARVC patients.
  • To identify novel genes associated with ARVC.
  • To characterize the functional impact of a novel desmin mutation (p.N116S) in ARVC.

Main Methods:

  • Genotyping of 22 ARVC patients for mutations in known desmosomal genes.
  • Screening for desmin mutations.
  • Functional analysis of the desmin p.N116S mutation using recombinant protein, atomic force microscopy, viscosimetry, and cell transfections (SW13 cells).

Main Results:

  • Disease-associated sequence variants were found in 43% of the ARVC cohort.
  • A novel desmin mutation, p.N116S, was identified in an ARVC patient with terminal heart failure.
  • The p.N116S mutation caused aggresome formation in cardiac and skeletal muscle and impaired desmin filament formation.
  • Cardiac aggresomes were prominent in the right ventricle.

Conclusions:

  • Desmin is identified as a novel gene associated with ARVC.
  • The p.N116S desmin mutation contributes to ARVC pathogenesis through impaired filament formation and aggresome accumulation.
  • Desmin should be included in molecular genetic screening for ARVC patients.

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