A novel de novo mutation in the desmin gene causes desmin myopathy with toxic aggregates

Sugawara, Masashiro; Kato, Kanefusa; Komatsu, Masatoshi; Wada, Christopher A.; Kawamura, Koichi; Shindo, Shoko; Yoshioka, Nobutaka; Tanaka, Keiko; Watanabe, Seiji; Toyoshima, Itaru

doi:10.1212/wnl.55.7.986

Cited by 60 publications

(41 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Additional cardiopathological findings have been reported based on examination of cardiac biopsies or explanted hearts. 37,43,52,56 In all described cases, microscopic examination revealed protein aggregates in the center of cardiac muscle fibre, rather than subsarcolemmally, hypertrophy of cardiomyocytes, prominent nuclei and considerable interstitial fibrosis (Fig. 8).…”

Section: Cardiac and Smooth Muscle Pathologymentioning

confidence: 83%

Intermediate Filament Diseases: Desminopathy

Goldfarb

Olivé

Vicart³

et al. 2008

Advances in Experimental Medicine and Biology

107

View full text Add to dashboard Cite

Desminopathy is one of the most common intermediate filament human disorders associated with mutations in closely interacting proteins, desmin and alphaB-crystallin. The inheritance pattern in familial desminopathy is characterized as autosomal dominant or autosomal recessive, but many cases have no family history. At least some and likely most sporadic desminopathy cases are associated with de novo DES mutations. The age of disease onset and rate of progression may vary depending on the type of inheritance and location of the causative mutation. Typically, the illness presents with lower and later upper limb muscle weakness slowly spreading to involve truncal, neckflexor, facial and bulbar muscles. Skeletal myopathy is often combined with cardiomyopathy manifested by conduction blocks, arrhythmias and chronic heart failure resulting in premature sudden death. Respiratory muscle weakness is a major complication in some patients. Sections of the affected skeletal and cardiac muscles show abnormal fibre areas containing chimeric aggregates consisting of desmin and other cytoskeletal proteins. Various DES gene mutations: point mutations, an insertion, small in-frame deletions and a larger exon-skipping deletion, have been identified in desminopathy patients. The majority of these mutations are located in conserved alpha-helical segments, but additional mutations have recently been identified in the tail domain. Filament and network assembly studies indicate that most but not all disease-causing mutations make desmin assembly-incompetent and able to disrupt a pre-existing filamentous network in dominant-negative fashion. AlphaBcrystallin serves as a chaperone for desmin preventing its aggregation under various forms of stress; mutant CRYAB causes cardiac and skeletal myopathies identical to those resulting from DES mutations.

show abstract

Section: Cardiac and Smooth Muscle Pathologymentioning

confidence: 83%

Intermediate Filament Diseases: Desminopathy

Goldfarb

Olivé

Vicart³

et al. 2008

Advances in Experimental Medicine and Biology

107

View full text Add to dashboard Cite

show abstract

“…Elevated creatinine kinase levels have been reported in some DRM patients. 4,15,25 The creatinine kinase level was normal in the 1 subject for whom that information was available (Arg350Trp mutation). In contrast to typical observations in DRM, severe conduction system disease and arrhythmias were absent.…”

Section: Phenotype Analysismentioning

confidence: 99%

“…Transfection of various DES mutations into cellular models has largely confirmed in vitro aggregation of desmin protein and disruption of the cytoplasmic filamentous desmin network. 4,5,8,9,11,[13][14][15] …”

mentioning

confidence: 99%

Prevalence of Desmin Mutations in Dilated Cardiomyopathy

et al. 2007

View full text Add to dashboard Cite

Background-Desmin-related myofibrillar myopathy (DRM) is a cardiac and skeletal muscle disease caused by mutations in the desmin (DES) gene. Mutations in the central 2B domain of DES cause skeletal muscle disease that typically precedes cardiac involvement. However, the prevalence of DES mutations in dilated cardiomyopathy (DCM) without skeletal muscle disease is not known. Methods and Results-Denaturing high-performance liquid chromatography was used to screen DES for mutations in 116 DCM families from the Familial Dilated Cardiomyopathy Registry and in 309 subjects with DCM from the Beta-Blocker Evaluation of Survival Trial (BEST). DES mutations were transfected into SW13 and human smooth muscle cells and neonatal rat cardiac myocytes, and the effects on cytoskeletal desmin network architecture were analyzed with confocal microscopy. Five novel missense DES mutations, including the first localized to the highly conserved 1A domain, were detected in 6 subjects (1.4%). Transfection of DES mutations in the 2B domain severely disrupted the fine intracytoplasmic staining of desmin, causing clumping of the desmin protein. A tail domain mutation (Val459Ile) showed milder effects on desmin cytoplasmic network formation and appears to be a low-penetrant mutation restricted to black subjects. Conclusions-The prevalence of DES mutations in DCM is between 1% and 2%, and mutations in the 1A helical domain, as well as the 2B rod domain, are capable of causing a DCM phenotype. The lack of severe disruption of cytoskeletal desmin network formation seen with mutations in the 1A and tail domains suggests that dysfunction of seemingly intact desmin networks is sufficient to cause DCM.

show abstract

“…Cytoplasmic IF proteins are known to exhibit aberrant organization and formation of IF aggregates in the form of inclusions as described for K8/K18 in alcoholic and nonalcoholic steatohepatitis (Zatloukal et al, 2007;Omary et al, 2009), glial fibrillary acidic protein in Alexander disease (Liem and Messing, 2009), and desmin in desmin-related myopathy (Sugawara et al, 2000). Similarly, the presence of nuclear lamin or cytoplasmic keratin aggregates (not inclusions per se, presumably due to the smaller-sized aggregates as compared to inclusions seen by standard hematoxylin and eosin staining) has been reported in several laminopathies (Dechat et al, 2008;Bertrand et al, 2011;Worman, 2012) and in the setting of epidermal keratin mutation in the Dowling-Meara form of epidermolysis bullosa simplex (Coulombe et al, 1991).…”

Section: Lamin-containing Aggregates Form In the Context Of Liver Injurymentioning

confidence: 99%

Lamin aggregation is an early sensor of porphyria-induced liver injury

Singla

Griggs

Kwan

et al. 2013

Journal of Cell Science

View full text Add to dashboard Cite

SummaryOxidative liver injury during steatohepatitis results in aggregation and transglutaminase-2 (TG2)-mediated crosslinking of the keratin cytoplasmic intermediate filament proteins (IFs) to form Mallory-Denk body (MDB) inclusions. The effect of liver injury on lamin nuclear IFs is unknown, though lamin mutations in several human diseases result in lamin disorganization and nuclear shape changes. We tested the hypothesis that lamins undergo aggregation during oxidative liver injury using two MDB mouse models: (i) mice fed the porphyrinogenic drug 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) and (ii) mice that harbor a mutation in ferrochelatase (fch), which converts protoporphyrin IX to heme. Dramatic aggregation of lamin A/C and B1 was noted in the livers of both models in association with changes in lamin organization and nuclear shape, as determined by immunostaining and electron microscopy. The lamin aggregates sequester other nuclear proteins including transcription factors and ribosomal and nuclear pore components into high molecular weight complexes, as determined by mass-spectrometry and confirmed biochemically. Lamin aggregate formation is rapid and precedes keratin aggregation in fch livers, and is seen in liver explants of patients with alcoholic cirrhosis. Exposure of cultured cells to DDC, protoporphyrin IX or Nmethyl-protoporphyrin, or incubation of purified lamins with protoporphyrin IX, also results in lamin aggregation. In contrast, lamin aggregation is ameliorated by TG2 inhibition. Therefore, lamin aggregation is an early sensor of porphyria-associated liver injury and might serve to buffer oxidative stress. The nuclear shape and lamin defects associated with porphyria phenocopy the changes seen in laminopathies and could result in transcriptional alterations due to sequestration of nuclear proteins.

show abstract

A novel de novo mutation in the desmin gene causes desmin myopathy with toxic aggregates

Abstract: A novel de novo mutation, L385P, causes desmin myopathy. An expression study indicated the toxic effect of the L385P mutation.

Cited by 60 publications

References 26 publications

Intermediate Filament Diseases: Desminopathy

Intermediate Filament Diseases: Desminopathy

Prevalence of Desmin Mutations in Dilated Cardiomyopathy

Lamin aggregation is an early sensor of porphyria-induced liver injury

Contact Info

Product

Resources

About