The novel desmin mutant p.A120D impairs filament formation, prevents intercalated disk localization, and causes sudden cardiac death

Andreas Brodehl*, Mareike Dieding, Bärbel Klauke, Eric Dec, Shrestha Madaan, Taosheng Huang, John Gargus, Azra Fatima, Tomo Šaric, Hamdin Cakar, Volker Walhorn, Katja Tönsing, Tim Skrzipczyk, Ramona Cebulla, Désirée Gerdes, Uwe Schulz, Jan Gummert, Jesper Hastrup Svendsen, Morten Salling Olesen, Dario AnselmettiAlex Hørby Christensen, Virginia Kimonis, Hendrik Milting

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

35 Scopus citations


Background-The intermediate filament protein desmin is encoded by the gene DES and contributes to the mechanical stabilization of the striated muscle sarcomere and cell contacts within the cardiac intercalated disk. DES mutations cause severe skeletal and cardiac muscle diseases with heterogeneous phenotypes. Recently, DES mutations were also found in patients with arrhythmogenic right ventricular cardiomyopathy. Currently, the cellular and molecular pathomechanisms of the DES mutations leading to this disease are not exactly known. Methods and Results-We identified the 2 novel variants DES-p.A120D (c.359C>A) and DES-p.H326R (c.977A>G), which were characterized by cell culture experiments and atomic force microscopy. Family analysis indicated a broad spectrum of cardiomyopathies with a striking frequency of arrhythmias and sudden cardiac deaths. The in vitro experiments of desmin-p.A120D reveal a severe intrinsic filament formation defect causing cytoplasmic aggregates in cell lines and of the isolated recombinant protein. Model variants of codon 120 indicated that ionic interactions contribute to this filament formation defect. Ex vivo analysis of ventricular tissue slices revealed a loss of desmin staining within the intercalated disk and severe cytoplasmic aggregate formation, whereas z-band localization was not affected. The functional experiments of desmin-p.H326R did not demonstrate any differences from wild type. Conclusions-Because of the functional in vivo and in vitro characterization, DES-p.A120D has to be regarded as a pathogenic mutation and DES-p.H326R as a rare variant with unknown significance. Presumably, the loss of the desmin-p. A120D filament localization at the intercalated disk explains its clinical arrhythmogenic potential.

Original languageEnglish (US)
Pages (from-to)615-623
Number of pages9
JournalCirculation: Cardiovascular Genetics
Issue number6
StatePublished - Dec 2013
Externally publishedYes


  • Arrhythmias
  • Cardiac
  • Cardiomyopathies
  • Death sudden
  • Desmin
  • Desmosomes
  • Intermediate filaments

ASJC Scopus subject areas

  • Genetics
  • Cardiology and Cardiovascular Medicine
  • Genetics(clinical)


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