Desmin myopathy, a skeletal myopathy with cardiomyopathy caused by mutations in the desmin gene.

Background: Myofibrillar myopathies are a heterogeneous group of inherited or sporadic skeletal myopathies associated with cardiomyopathy. Among the m yofibrillar proteins that accumulate within the muscle fibers of affected p atients, the one found most consistently is desmin, an intermediate-filamen t protein responsible for the structural integrity of the myofibrils. Skele tal 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 diseas e and analyzed the desmin gene for mutations, using complementary DNA (cDNA ) amplified from muscle-biopsy specimens and genomic DNA extracted from blo od lymphocytes. Restriction-enzyme analysis was used to confirm the mutatio ns. Expression vectors containing normal or mutant desmin cDNA were introdu ced into cultured cells to determine whether the mutant desmin formed inter mediate filaments. Results: Six missense mutations in the coding region of the desmin gene tha t cause the substitution of an amino acid were identified in 11 patients (1 0 members of 4 families and 1 patient with sporadic disease); a splicing de fect that resulted in the deletion of exon 3 was identified in the other pa tient with sporadic disease. Mutations were clustered in the carboxy-termin al part of the rod domain, which is critical for filament assembly. In tran sfected cells, the mutant desmin was unable to form a filamentous network. Seven of the 12 patients with mutations in the desmin gene had cardiomyopat hy. 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 myofibril s and severe dysfunction of skeletal and cardiac muscles. (N Engl J Med 200 0;342:770-80.) (C)2000, Massachusetts Medical Society.