Tragedy in a heartbeat: malfunctioning desmin causes skeletal and cardiac muscle disease

Goldfarb, Lev G.; Dalakas, Marinos C.

doi:10.1172/jci38027

Cited by 192 publications

(178 citation statements)

References 79 publications

(124 reference statements)

Supporting

Mentioning

155

Contrasting

Unclassified

Order By: Relevance

“…9 Right ventricular cardiomyopathy and ARVC that were present in individuals of this family have been linked to DES mutations in recent years. [10][11][12][13] In conclusion, we have, by means of exome sequencing, identified the causative DES mutation in a family with MFM and ARVC.…”

Section: Discussionmentioning

confidence: 85%

Autosomal dominant myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopathy 7 is caused by a DES mutation

et al. 2012

View full text Add to dashboard Cite

Using exome sequencing we searched for the genetic cause of autosomal dominant myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopathy (ARVC) in a Swedish family. A heterozygous C-to-T transition, c.1255C>T, p.Pro419Ser in the desmin gene on chromosome 2q35, was identified. Previous studies had demonstrated linkage to chromosome 10q22.3, but no causative mutation had been found in that region. Sanger sequencing of DNA from 17 family members confirmed the heterozygous c.1255C>T desmin mutation in seven out of ten family members that had been classified as affected in the previous study. Our new results demonstrate the usefulness of next-generation sequencing, and the diagnostic difficulties with some forms of dominantly inherited muscle diseases as they can display a wide clinical and morphological variability even within a given family. European Journal of Human Genetics (2012) 20, 984-985; doi:10.1038/ejhg.2012.39; published online 7 March 201

show abstract

Section: Discussionmentioning

confidence: 85%

Autosomal dominant myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopathy 7 is caused by a DES mutation

et al. 2012

View full text Add to dashboard Cite

show abstract

“…Beyond CASQ2, CRYAB and DESMIN (not shown) were identified as maturation genes. Desmin is a major intermediate filament protein in cardiomyocytes and CRYAB (aBcrystallin) is the chaperone for folding Desmin [36]. Desmin is expressed early in the heart during embryogenesis, but the levels of expression continue to increase during development [37].…”

Section: Babiarz Et Almentioning

confidence: 99%

Determination of the Human Cardiomyocyte mRNA and miRNA Differentiation Network by Fine-Scale Profiling

Babiarz

Ravon

Sridhar

et al. 2012

Stem Cells and Development

View full text Add to dashboard Cite

To gain insight into the molecular regulation of human heart development, a detailed comparison of the mRNA and miRNA transcriptomes across differentiating human-induced pluripotent stem cell (hiPSC)-derived cardiomyocytes and biopsies from fetal, adult, and hypertensive human hearts was performed. Gene ontology analysis of the mRNA expression levels of the hiPSCs differentiating into cardiomyocytes revealed 3 distinct groups of genes: pluripotent specific, transitional cardiac specification, and mature cardiomyocyte specific. Hierarchical clustering of the mRNA data revealed that the transcriptome of hiPSC cardiomyocytes largely stabilizes 20 days after initiation of differentiation. Nevertheless, analysis of cells continuously cultured for 120 days indicated that the cardiomyocytes continued to mature toward a more adult-like gene expression pattern. Analysis of cardiomyocyte-specific miRNAs (miR-1, miR-133a/b, and miR-208a/b) revealed an miRNA pattern indicative of stem cell to cardiomyocyte specification. A biostatistitical approach integrated the miRNA and mRNA expression profiles revealing a cardiomyocyte differentiation miRNA network and identified putative mRNAs targeted by multiple miRNAs. Together, these data reveal the miRNA network in human heart development and support the notion that overlapping miRNA networks re-enforce transcriptional control during developmental specification.

show abstract

“…Desmin's essential role was underscored by showing that mutations in the desmin gene ( DES ) (chromosome 2q35) cause myopathies and cardiomyopathies 6. To date, more than 67 disease‐causing DES mutations have been detected in human myofibrillar diseases 6, 7, 8.…”

Section: Introductionmentioning

confidence: 99%

“…To date, more than 67 disease‐causing DES mutations have been detected in human myofibrillar diseases 6, 7, 8. Desmin‐related cardiomyopathy (DRC) is a family of genetic disorders caused by mutations in desmin and other desmin‐related proteins that results in a spectrum of myofibrillar myopathies.…”

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

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

Tragedy in a heartbeat: malfunctioning desmin causes skeletal and cardiac muscle disease

Cited by 192 publications

References 79 publications

Autosomal dominant myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopathy 7 is caused by a DES mutation

Autosomal dominant myofibrillar myopathy with arrhythmogenic right ventricular cardiomyopathy 7 is caused by a DES mutation

Determination of the Human Cardiomyocyte mRNA and miRNA Differentiation Network by Fine-Scale Profiling

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

Contact Info

Product

Resources

About