Missense mutations in desmin associated with familial cardiac and skeletal myopathy

Abstract

Desmin-related myopathy (OMIM 601419) is a familial disorder characterized by skeletal muscle weakness associated with cardiac conduction blocks, arrhythmias and restrictive heart failure, and by intracytoplasmic accumulation of desmin-reactive deposits in cardiac and skeletal muscle cells. The underlying molecular mechanisms are unknown. Involvement of the desmin gene (DES) has been excluded in three families diagnosed with desmin-related myopathy. We report two new families with desmin-related cardioskeletal myopathy associated with mutations in the highly conserved carboxy-terminal end of the desmin rod domain. A heterozygous A337P mutation was identified in a family with an adult-onset skeletal myopathy and mild cardiac involvement. Compound heterozygosity for two other mutations, A360P and N393I, was detected in a second family characterized by childhood-onset aggressive course of cardiac and skeletal myopathy.

Intermediate Filament Diseases: Desminopathy

“…40 Indeed, in a family segregating both p.Ala360Pro and p.Asn393Ile mutations, a highly aggressive early onset cardioskeletal myopathy affected only those having both mutations in a compound heterozygous fashion but spared the carriers of either mutation. 9 The p.Ala337Pro, p.Leu338Arg, p.Asp399Tyr, p.Glu401Lys and p.Arg406Trp mutations alone make desmin filaments dysfunctional and cause increasingly more severe disease that starts earlier and leads to the development of life-threatening dysphagia, cardiomyopathy, or respiratory weakness. 40 The severity of illness caused by the mutations located in the C-terminal part of the 2B alphahelical domain can be explained by structural relationships these mutations potentially disrupt.…”

“…9 They presented with syncopal episodes and complete heart block requiring insertion of a permanent pacemaker at the age of 2, 9 and 10 years. EchoCG showed moderate to severe biatrial dilatation but normal ventricle size.…”

“…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.…”

Aberrant Mitochondrial Fission Is Maladaptive in Desmin Mutation–Induced Cardiac Proteotoxicity

“…The mutant desmin transgenic mouse (D7‐Des Tg) carries a 7 amino acid deletion R172‐E178 in DES and provides a clinically relevant mouse model of cardiac proteotoxicity 9, 10, 11, 12. This model manifests a collapse of the desmin network, and accumulation of desmin aggregates, which contributes to cardiomyopathy 10.…”

Genetic disorders involving molecular-chaperone genes: A perspective

“…76 Mutations in the desmin gene have been implicated in pathogenesis. 77 Another gene affected (mutation R120G) is named CRYAB; it encodes alpha-B-crystallin and maps to chromosome 11q21-23. 67 The product of the defective gene R120G showed decreased beta-sheet secondary structure, with reduction, or lackdepending on the substrate used in the assay-of chaperone activity in vitro.…”