Article

Desmin myopathy

National Institutes of Health, Bethesda, MD 20892-1361, USA.
Brain (Impact Factor: 10.23). 05/2004; 127(Pt 4):723-34. DOI: 10.1093/brain/awh033
Source: PubMed

ABSTRACT Desmin myopathy is a recently identified disease associated with mutations in desmin or alphaB-crystallin. Typically, the illness presents with lower limb muscle weakness slowly spreading to involve truncal, neck-flexor, facial, bulbar and respiratory muscles. Skeletal myopathy is often combined with cardiomyopathy manifested by conduction blocks and arrhythmias resulting in premature sudden death. Sections of the affected skeletal and cardiac muscles show abnormal fibre areas containing amorphous eosinophilic deposits seen as granular or granulofilamentous material on electron microscopic examination. Immuno-staining for desmin is positive in each region containing abnormal structures. The inheritance pattern in familial desmin myopathy is autosomal dominant or autosomal recessive, but many cases have no family history. At least some, and probably most, non-familial desmin myopathy cases are associated with de novo desmin mutations. Age of disease onset and rate of progression may vary depending on the type of inheritance and location of the causative mutation. Multiple mutations have been identified in the desmin gene: point substitutions, insertion, small in-frame deletions and a larger exon-skipping deletion. The majority of these mutations are located in conserved alpha-helical segments of desmin. Many of the missense mutations result in changing the original amino acid into proline, which is known as a helix breaker. Studies of transfected cell cultures indicate that mutant desmin is assembly-incompetent and able to disrupt a pre-existing filamentous network in dominant-negative fashion. Disease-associated desmin mutations in humans or transgenic mice cause accumulation of chimeric intracellular aggregates containing desmin and other cytoskeletal proteins. alphaB-crystallin serves in the muscle as a chaperone preventing desmin aggregation under various forms of stress. If mutated, alphaB-crystallin may cause a myopathy similar to those resulting from desmin mutations. Routine genetic testing of patients for mutations in desmin and alphaB- crystallin genes is now available and necessary for establishing an accurate diagnosis and providing appropriate genetic counselling. Better understanding of disease pathogenesis would stimulate research focused on developing specific treatments for these conditions.

Download full-text

Full-text

Available from: Lev G Goldfarb, Sep 23, 2014
0 Followers
 · 
127 Views
  • Source
    • "AGEs and lipid peroxidation end-products accumulate in PAD muscle and, particularly, in PAD myofibers (Norgren et al. 2007; Pipinos et al. 2008, 2007). Desmin links neighboring myofibrils into bundles through their Z-discs (Capetanaki et al. 2007; Dalakas et al. 2000), aligns the Z-discs of neighboring myofibers (Capetanaki et al. 1997; Carlsson and Thornell 2001; Lazarides 1980), organizes the mitochondria into a welldefined functional network around the myofibrils (Capetanaki et al. 1997; Milner et al. 2000) and facilitates transmission of the force of sarcomere contraction to the ECM (Bloch and Gonzalez-Serratos 2003; Capetanaki et al. 2007; Carlsson and Thornell 2001; Goldfarb et al. 2004; Paulin et al. 2004). Mitochondrial dysfunction in PAD skeletal muscle is well documented (Makris et al. 2007; Pipinos et al. 2006; Pipinos et al. 2003; Pipinos et al. 2000). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Patients with peripheral artery disease (PAD) develop a myopathy in their ischemic lower extremities, which is characterized by myofiber degeneration, mitochondrial dysfunction and impaired limb function. Desmin, a protein of the cytoskeleton, is central to maintenance of the structure, shape and function of the myofiber and its organelles, especially the mitochondria, and to translation of sarcomere contraction into muscle contraction. In this study, we investigated the hypothesis that disruption of the desmin network occurs in gastrocnemius myofibers of PAD patients and correlates with altered myofiber morphology, mitochondrial dysfunction, and impaired limb function. Using fluorescence microscopy, we evaluated desmin organization and quantified myofiber content in the gastrocnemius of PAD and control patients. Desmin was highly disorganized in PAD but not control muscles and myofiber content was increased significantly in PAD compared to control muscles. By qPCR, we found that desmin gene transcripts were increased in the gastrocnemius of PAD patients as compared with control patients. Increased desmin and desmin gene transcripts in PAD muscles correlated with altered myofiber morphology, decreased mitochondrial respiration, reduced calf muscle strength and decreased walking performance. In conclusion, our studies identified disruption of the desmin system in gastrocnemius myofibers as an index of the myopathy and limitation of muscle function in patients with PAD.
    Journal of Histochemistry and Cytochemistry 01/2015; DOI:10.1369/0022155415569348 · 2.40 Impact Factor
  • Source
    • "MATR3 (MIM# 164015) have recently been reported as the underlying causes of dominant distal myopathy [Senderek et al., 2009]. Desminopathy and other forms of myofibrillar myopathy are caused by mutations in the DES gene (MIM# 125660) with both autosomal dominant and recessive inheritance [Goldfarb et al., 2004; Arias et al., 2006]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Both peripheral neuropathy and distal myopathy are well-established inherited neuromuscular disorders characterized by progressive weakness and atrophy of the distal limb muscles. A complex phenotype of peripheral neuropathy, myopathy, hoarseness, and hearing loss was diagnosed in a large autosomal dominant Korean family. A high density single nucleotide polymorphism (SNP)-based linkage study mapped the underlying gene to a region on chromosome 19q13.3. The maximum multipoint LOD score was 3.794. Sequencing of 34 positional candidate genes in the segregating haplotype revealed a novel c.2822G>T (p.Arg941Leu) mutation in the gene MYH14, which encodes the nonmuscle myosin heavy chain 14. Clinically we observed a sequential pattern of the onset of muscle weakness starting from the anterior to the posterior leg muscle compartments followed by involvement of intrinsic hand and proximal muscles. The hearing loss and hoarseness followed the onset of distal muscle weakness. Histopathologic and electrodiagnostic studies revealed both chronic neuropathic and myopathic features in the affected patients. Although mutations in MYH14 have been shown to cause nonsyndromic autosomal dominant hearing loss (DFNA4), the peripheral neuropathy, myopathy, and hoarseness have not been associated with MYH14. Therefore, we suggest that the identified mutation in MYH14 significantly expands the phenotypic spectrum of this gene.
    Human Mutation 06/2011; 32(6):669-77. DOI:10.1002/humu.21488 · 5.05 Impact Factor
  • Source
    • "IF mutations cause or predispose to more than 30 human diseases, including skin diseases, muscular dystrophies, premature aging, amyotrophic lateral sclerosis, and end-stage liver disease (Omary et al. 2004). IF inclusions are characteristically seen in association with several liver, neuronal, or muscle disorders (Kurt et al. 2004; Goldfarb et al. 2004; Cairns et al. 2004). Among the large protein family of IFs, vimentin is one of the most familiar members, as it is the major IF protein in mesenchymal cells. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Oxidative stress can be a significant cause of cell death and apoptosis. We performed studies in HepG2 cells to explore whether prior exposure to oxidative stress ("oxidative preconditioning") and geldanamycin (GA) treatment can protect the cell from damage caused by subsequent oxidative insults. The cells were treated with 10 nM GA for 24 h before oxidative stress. Oxidative preconditioning was achieved by 2 h exposures to H(2)O(2) (50 microM) separated by a 10-h recovery period in normal culture medium. Oxidative stress was induced by exposure to 500 microM H(2)O(2) for 24 h. The effects of GA and oxidative preconditioning were investigated on the formation of Hsp90, vimentin, insoluble vimentin aggregates, and cleavage of vimentin in a cell culture model of oxidative stress. GA treatment leads to enhanced expression of Hsp90 and vimentin and to inhibition of vimentin protein aggregation. Similar results were obtained by oxidative preconditioning. It is confirmed that low concentrations of GA protected HepG2 cells from subsequent oxidative stress by increasing the levels of Hsp90 and by alleviating the extent of cell apoptosis induced by oxidative stress, which is similar to oxidative preconditioning. However, in contrast to preconditioning, GA treatment obviously changed binding activity of Hsp90 to vimentin cleavages. All the above indicated that low concentrations of GA treatment triggered cell protection from oxidative stress. Both the level of Hsp90 and its ability to bind with vimentin were changed by low concentrations of GA and might contribute to oxidative stress protection.
    Cell Stress and Chaperones 02/2009; 14(4):381-9. DOI:10.1007/s12192-008-0092-7 · 2.54 Impact Factor
Show more