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A dysfunctional desmin mutation in a patient with severe generalized myopathy
A M Muñoz-Mármol1, G Strasser, M Isamat
1Fundación Echevarne, 08037 Barcelona, Spain.
Abstract:
Mice lacking desmin produce muscle fibers with Z disks and normal sarcomeric organization. However, the muscles are mechanically fragile and degenerate upon repeated contractions. We report here a human patient with severe generalized myopathy and aberrant intrasarcoplasmic accumulation of desmin intermediate filaments. Muscle tissue from this patient lacks the wild-type desmin allele and has a desmin gene mutation encoding a 7-aa deletion within the coiled-coil segment of the protein. We show that recombinant desmin harboring this deletion cannot form proper desmin intermediate filament networks in cultured cells, nor is it able to assemble into 10-nm filaments in vitro. These findings provide direct evidence that a mutation in desmin can cause human myopathies.
Insights
A mutation in the desmin gene causes a severe human myopathy. This genetic defect prevents proper desmin intermediate filament formation, leading to fragile muscles.
Area of Science:
- Muscle biology
- Genetics
- Cellular biology
Background:
- Desmin is a crucial intermediate filament protein in muscle fibers, essential for maintaining sarcomeric organization and mechanical stability.
- Mice lacking desmin exhibit mechanically fragile muscles that degenerate upon repeated contractions, highlighting desmin's importance.
Observation:
- A human patient presented with severe generalized myopathy and abnormal accumulation of desmin intermediate filaments within muscle cells.
- Muscle tissue analysis revealed the absence of the wild-type desmin allele and a specific mutation in the desmin gene.
Findings:
- The identified desmin gene mutation involves a 7-amino acid deletion within the protein's coiled-coil segment.
- Recombinant desmin with this deletion failed to form proper intermediate filament networks in cultured cells and could not assemble into 10-nm filaments in vitro.
Implications:
- This study provides direct evidence linking a specific desmin mutation to the pathogenesis of human myopathies.
- Understanding desmin's role in filament formation is critical for diagnosing and potentially treating desmin-related myopathies.