[HTML][HTML] Desmin myopathy, a skeletal myopathy with cardiomyopathy caused by mutations in the desmin gene

MC Dalakas, KY Park, C Semino-Mora… - … England Journal of …, 2000 - Mass Medical Soc
MC Dalakas, KY Park, C Semino-Mora, HS Lee, K Sivakumar, LG Goldfarb
New England Journal of Medicine, 2000Mass Medical Soc
Background Myofibrillar myopathies are a heterogeneous group of inherited or sporadic
skeletal myopathies associated with cardiomyopathy. Among the myofibrillar proteins that
accumulate within the muscle fibers of affected patients, the one found most consistently is
desmin, an intermediate-filament protein responsible for the structural integrity of the
myofibrils. Skeletal and cardiac myopathy develops in mice that lack desmin, suggesting that
mutations in the desmin gene may be pathogenic. Methods We examined 22 patients from 8 …
Background
Myofibrillar myopathies are a heterogeneous group of inherited or sporadic skeletal myopathies associated with cardiomyopathy. Among the myofibrillar proteins that accumulate within the muscle fibers of affected patients, the one found most consistently is desmin, an intermediate-filament protein responsible for the structural integrity of the myofibrils. Skeletal and cardiac myopathy develops in mice that lack desmin, suggesting that mutations in the desmin gene may be pathogenic.
Methods
We examined 22 patients from 8 families with dominantly inherited myofibrillar or desmin-related myopathy and 2 patients with sporadic disease and analyzed the desmin gene for mutations, using complementary DNA (cDNA) amplified from muscle-biopsy specimens and genomic DNA extracted from blood lymphocytes. Restriction-enzyme analysis was used to confirm the mutations. Expression vectors containing normal or mutant desmin cDNA were introduced into cultured cells to determine whether the mutant desmin formed intermediate filaments.
Results
Six missense mutations in the coding region of the desmin gene that cause the substitution of an amino acid were identified in 11 patients (10 members of 4 families and 1 patient with sporadic disease); a splicing defect that resulted in the deletion of exon 3 was identified in the other patient with sporadic disease. Mutations were clustered in the carboxy-terminal part of the rod domain, which is critical for filament assembly. In transfected cells, the mutant desmin was unable to form a filamentous network. Seven of the 12 patients with mutations in the desmin gene had cardiomyopathy.
Conclusions
Mutations in the desmin gene affecting intermediate filaments cause a distinct myopathy that is often associated with cardiomyopathy and is termed “desmin myopathy.” The mutant desmin interferes with the normal assembly of intermediate filaments, resulting in fragility of the myofibrils and severe dysfunction of skeletal and cardiac muscles.
The New England Journal Of Medicine