Sporadic cardiac and skeletal myopathy caused by a de novo desmin mutation

Desmin myopathy is a familial or sporadic disorder characterized by intracy toplasmic accumulation of desmin in the muscle cells. We and others have pr eviously identified desmin gene mutations in patients with familial myopath y, but close to 45% of the patients do not report previous family history o f the disease. The present study was conducted to determine the cause of de smin myopathy in a sporadic patient presenting with symmetrical muscle weak ness and atrophy combined with atrioventricular conduction block requiring a permanent pacemaker. A novel heterozygous R406W mutation in the desmin ge ne was identified by sequencing cDNA anti genomic DNA. Expression of a cons truct containing the patient's mutant desmin cDNA in SW13 (vim-) cells demo nstrated a high pathogenic potential of the R406W mutation. This mutation w as not found in the patient's father, mother or sister by sequencing and re striction analysis. Testing with five microsatellite markers and four intra genic single nucleotide polymorphisms excluded alternative paternity. Haplo type analysis indicates that the patient's father was germ-line mosaic for the desmin mutation. We conclude that de novo mutations in the desmin gene may be the cause of sporadic forms of desmin-related cardiac and skeletal m yopathy.