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Conspicuous involvement of desmin tail mutations in diverse cardiac and skeletal myopathies

Harald Bär1, Bertrand Goudeau, Sarah Wälde

  • 1Department of Cardiology, University of Heidelberg, Heidelberg, Germany.

Human Mutation
|January 16, 2007
PubMed

Insights

Mutations in the desmin (DES) gene's tail domain disrupt intermediate filament formation, causing desminopathy. These desmin mutations show incompatibility with wild-type desmin, impacting muscle cell structure and function.

Area of Science:

  • Muscle biology
  • Cellular and molecular biology
  • Genetics

Background:

  • Myofibrillar myopathies (MFM) are a group of genetic muscle disorders.
  • Mutations in the desmin (DES) gene cause severe desminopathy, affecting cardiac, skeletal, and smooth muscles.
  • Most known mutations are in the desmin rod domain; this study focuses on the tail domain.

Observation:

  • Three novel and four previously described desmin tail domain mutations were analyzed.
  • Mutant desmin proteins were studied for in vitro filament formation and cytoskeletal array assembly in myoblasts.
  • Viscometric assembly assays revealed significant differences in filament properties compared to wild-type desmin.

Findings:

  • Most tail domain mutants assembled into intermediate filaments (IFs) in vitro and were incorporated into IF arrays in transfected cells.
  • Mutants displayed altered filament formation competence and filament-filament interactions when coassembled with wild-type desmin.
  • An inherent incompatibility between mutant and wild-type desmin proteins was observed in mixed filaments.

Implications:

  • Desmin tail domain mutations can lead to desminopathy by disrupting cytoskeletal structure and function.
  • Altered interactions with other cytoskeletal components may explain diverse clinical phenotypes.
  • In vitro assembly assays are effective for identifying desmin mutations that cause filament abnormalities.

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