A Missense Mutation in the Desmin Rod Domain Is Associated with Autosomal Dominant Distal Myopathy, and Exerts a Dominant Negative Effect on Filament Formation

Abstract

In some myopathies of distal onset, the intermediate filament desmin is abnormally accumulated in skeletal and cardiac muscle. We report the first point mutation in desmin cosegregating with an autosomal dominant form of desmin-related myopathy. The L345P desmin missense mutation occurs in a large, six generation Ashkenazi Jewish family. The mutation is located in an evolutionarily highly conserved position of the desmin coiled-coil rod domain important for dimer formation. L345P desmin is incapable of forming filamentous networks in transfected HeLa and SW13 cells. We conclude that the L345P desmin missense mutation causes myopathy by interfering in a dominant-negative manner with the dimerization-polymerization process of intermediate filament assembly.

Intermediate Filament Diseases: Desminopathy

“…83 It has been conclusively shown that pathogenic mutant desmin disrupts a preexisting filamentous network in a dominant-negative fashion. 6,53,84 But some mutations located in the nonalpha-helical tail domain of the desmin molecule do not interfere with the initial IF assembly steps. Thus, the p.Thr442Ile, p.Lys449Thr, p.Ile451Met and p.Val469Met mutants, but not p.Arg454Trp and p.Ser460Ile, formed a filamentous network in SW13 cells.…”

“…37,46,55 Skeletal muscle weakness followed by cardiomyopathy was observed in 31 patients from 20 families ( Table 2). A p.Leu345Pro mutation within the 2B helix 6 was detected in a family that included 16 members suffering from gait disturbances caused by bilateral weakness in distal leg muscles that progressed to all limbs and bulbar, respiratory and facial muscles. 101 Many of the surviving patients were confined to a wheelchair or using a walker 7 to 20 years after disease onset.…”

“…Immunohistochemical studies have consistently demonstrated the presence of inclusions or deposits reacting with antibodies against desmin and other proteins such as alphaB-crystallin and, although rarely investigated, synemin, 42,85,97 syncoilin, 109 plectin, 42,43 nestin, 6,85 dystrophin, 2,43,50 merosin, alpha-and beta-dystroglycan, alpha-, beta-, gamma-and deltasarcoglycans, utrophin, collagen VI, NOS, caveolin, dysferlin, beta-and gamma-laminin, actin, actinin, N-CAM, heat shock protein 72/73, 43 myotilin, 2,43,50 gamma-filamin, 50 vimentin, beta-spectrin 11 and ubiquitin.. 43,50,102 The size, shape and localization of protein aggregates differ from one case to another. These may be restricted to the subsarcolemmal regions or within the cytoplasm; they may be diffuse or well demarcated, and in some cases both diffuse and well demarcated small deposits are found in the same specimen (Fig.…”

“…1,2 Transfected into cell cultures, many but not all mutant desmins are incapable of generating an intracellular filamentous network [3][4][5] and disrupt pre-existing endogenous intermediate filament structures. 6 Disease-associated DES mutations expressed in transgenic mice cause an accumulation of chimeric intracellular aggregates containing desmin and other cytoskeletal proteins. Misfolded desmin resists turnover by the cellular enzymatic machinery.…”

“…Misfolded desmin resists turnover by the cellular enzymatic machinery. 7 Identification of multiple causative mutations in the DES gene 6,[9][10][11] helped to establish desminopathy as a distinct disease. The second genetically independent subset of desminopathy is myopathy associated with mutations in CRYAB, a chaperone that normally stabilizes proteins including desmin and prevents their irreversible aggregation.…”