BACKGROUND: Desmin-related myofibrillar myopathy (DRM) is a cardiac and skeletal 
muscle disease caused by mutations in the desmin (DES) gene. Mutations in the 
central 2B domain of DES cause skeletal muscle disease that typically precedes 
cardiac involvement. However, the prevalence of DES mutations in dilated 
cardiomyopathy (DCM) without skeletal muscle disease is not known.
METHODS AND RESULTS: Denaturing high-performance liquid chromatography was used 
to screen DES for mutations in 116 DCM families from the Familial Dilated 
Cardiomyopathy Registry and in 309 subjects with DCM from the Beta-Blocker 
Evaluation of Survival Trial (BEST). DES mutations were transfected into SW13 
and human smooth muscle cells and neonatal rat cardiac myocytes, and the effects 
on cytoskeletal desmin network architecture were analyzed with confocal 
microscopy. Five novel missense DES mutations, including the first localized to 
the highly conserved 1A domain, were detected in 6 subjects (1.4%). Transfection 
of DES mutations in the 2B domain severely disrupted the fine intracytoplasmic 
staining of desmin, causing clumping of the desmin protein. A tail domain 
mutation (Val459Ile) showed milder effects on desmin cytoplasmic network 
formation and appears to be a low-penetrant mutation restricted to black 
subjects.
CONCLUSIONS: The prevalence of DES mutations in DCM is between 1% and 2%, and 
mutations in the 1A helical domain, as well as the 2B rod domain, are capable of 
causing a DCM phenotype. The lack of severe disruption of cytoskeletal desmin 
network formation seen with mutations in the 1A and tail domains suggests that 
dysfunction of seemingly intact desmin networks is sufficient to cause DCM.