Desmin Myopathy, a Skeletal Myopathy with Cardiomyopathy Caused by Mutations in the Desmin Gene

Dalakas, Marinos C.; Park, Kye-Yoon; Semino–Mora, Cristina; Lee, Hee Suk; Sivakumar, Kumaraswamy; Goldfarb, Lev G.

doi:10.1056/nejm200003163421104

Cited by 407 publications

(328 citation statements)

References 29 publications

Supporting

Mentioning

306

Contrasting

Unclassified

Order By: Relevance

“…Desmin mutations can result in various myopathies that are characterized by desmin network disorganization, accumulation of insoluble desmin‐containing aggregates, and sarcomere disarray 9, 36, 37. Expression of the 7 amino acid deletion (R173–E179) mutation in desmin leads to a desminopathy characterized by defects in skeletal, cardiac, and smooth muscle 38, 39.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

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

Alam

Abdullah

Aishwarya

et al. 2018

JAHA

View full text Add to dashboard Cite

BackgroundDesmin filament proteins interlink the contractile myofibrillar apparatus with mitochondria, nuclei and the sarcolemma. Mutations in the human desmin gene cause cardiac disease, remodeling, and heart failure but the pathophysiological mechanisms remain unknown.Methods and ResultsCardiomyocyte‐specific overexpression of mutated desmin (a 7 amino acid deletion R172‐E178, D7‐Des Tg) causes accumulations of electron‐dense aggregates and myofibrillar degeneration associated with cardiac dysfunction. Though extensive studies demonstrated that these altered ultrastructural changes cause impairment of cardiac contractility, the molecular mechanism of cardiomyocyte death remains elusive. In the present study, we report that the D7‐Des Tg mouse hearts undergo aberrant mitochondrial fission associated with increased expression of mitochondrial fission regulatory proteins. Mitochondria isolated from D7‐Des Tg hearts showed decreased mitochondrial respiration and increased apoptotic cell death. Overexpression of mutant desmin by adenoviral infection in cultured cardiomyocytes led to increased mitochondrial fission, inhibition of mitochondrial respiration, and activation of cellular toxicity. Inhibition of mitochondrial fission by mitochondrial division inhibitor mdivi‐1 significantly improved mitochondrial respiration and inhibited cellular toxicity associated with D7‐Des overexpression in cardiomyocytes.ConclusionsAberrant mitochondrial fission results in mitochondrial respiratory defects and apoptotic cell death in D7‐Des Tg hearts. Inhibition of aberrant mitochondrial fission using mitochondrial division inhibitor significantly preserved mitochondrial function and decreased apoptotic cell death. Taken together, our study shows that maladaptive aberrant mitochondrial fission causes desminopathy‐associated cellular dysfunction.

show abstract

Section: Discussionmentioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

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

Alam

Abdullah

Aishwarya

et al. 2018

JAHA

View full text Add to dashboard Cite

show abstract

“…Analysis of clinical/ pathological characteristics of desminopathy outlined several sometimes overlapping clinical forms. 96 …”

Section: Clinical Manifestations Definitions Of Desminopathymentioning

confidence: 99%

“…96 Cardiomyopathy, smooth muscle myopathy, neuropathy, respiratory dysfunction, facial paralysis or cataracts may be present in some cases and absent in others. With few exceptions, phenotypic manifestations in members of the same family were concordant, making it likely that the type and location of the mutation within the desmin molecule influences the phenotype.…”

Section: Correlation Between Genotype and Phenotypementioning

confidence: 99%

“…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.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Intermediate Filament Diseases: Desminopathy

Goldfarb

Olivé

Vicart³

et al. 2008

Advances in Experimental Medicine and Biology

Self Cite

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

Desmin

Nuckolls¹

2002

Wiley Encyclopedia of Molecular Medicine

View full text Add to dashboard Cite

Desmin Myopathy, a Skeletal Myopathy with Cardiomyopathy Caused by Mutations in the Desmin Gene

Cited by 407 publications

References 29 publications

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

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

Intermediate Filament Diseases: Desminopathy

Desmin

Contact Info

Product

Resources

About