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Severe muscle disease-causing desmin mutations interfere with in vitro filament assembly at distinct stages

Harald Bär1, Norbert Mücke, Anna Kostareva

  • 1Department of Molecular Genetics, German Cancer Research Center, D-69120 Heidelberg, Germany.

Proceedings of the National Academy of Sciences of the United States of America
|October 12, 2005
PubMed

Insights

Mutations in the desmin gene cause desmin-related myopathy (DRM) by disrupting intermediate filament (IF) assembly. Some desmin mutations prevent IF formation, while others allow IF assembly but still lead to protein aggregation in muscle cells.

Area of Science:

  • Muscle biology
  • Cellular and molecular biology
  • Biochemistry

Background:

  • Desmin is the primary intermediate filament (IF) protein in muscle cells.
  • Mutations in the desmin gene cause desmin-related myopathy (DRM), a condition characterized by skeletal and cardiac muscle dysfunction.
  • The precise impact of desmin mutations on filament assembly and cytoskeletal integration remains unclear, despite causing desmin aggregation.

Purpose of the Study:

  • To investigate how mutations in the desmin alpha-helical rod domain affect recombinant desmin assembly in vitro.
  • To examine the filament-forming capacity of desmin mutants in cDNA-transfected cells.
  • To elucidate the molecular mechanisms underlying desmin aggregation in desmin-related myopathy.

Main Methods:

  • In vitro assembly assays using recombinant desmin proteins with mutations in the alpha-helical rod domain.
  • cDNA transfection of cells to assess the filament-forming capacity of mutant desmin proteins.
  • Microscopic analysis of intermediate filament (IF) formation and aggregate structures in transfected cells.

Main Results:

  • Six out of fourteen desmin mutants successfully assembled into intermediate filaments (IFs) in vitro.
  • The remaining eight mutants exhibited defects at various stages of IF assembly, including tetramer formation, unit-length filament (ULF) formation, elongation, and maturation.
  • Mutants with in vitro assembly defects formed dot-like aggregates in transfected cells, while those that assembled into IFs appeared to form a normal IF cytoskeleton within the cellular context.

Conclusions:

  • Desmin mutations differentially impact in vitro and in vivo intermediate filament (IF) assembly.
  • Mutations causing in vitro assembly defects lead to aggregate formation in cells.
  • The mechanism by which desmin mutants that assemble normally in vitro still cause aggregation in myocytes requires further investigation and may provide insights into desmin-related myopathy (DRM) pathogenesis.

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