A missense mutation in the desmin rod domain is associated with autosomal dominant distal myopathy, and exerts a dominant negative effect on filamentformation

In some myopathies of distal onset, the intermediate filament desmin is abn ormally accumulated in skeletal and cardiac muscle. We report the first poi nt mutation in desmin cosegregating with an autosomal dominant form of desm in-related myopathy, The L345P desmin missense mutation occurs in a large, six generation Ashkenazi Jewish family. The mutation is located in an evolu tionarily highly conserved position of the desmin coiled-coil rod domain im portant for dimer formation. L345P desmin is incapable of forming filamento us networks in transfected HeLa and SW13 cells. We conclude that the L345P desmin missense mutation causes myopathy by interfering in a dominant-negat ive manner with the dimerization-polymerization process of intermediate fil ament assembly.