Functional characterization of novel alpha-helical rod domain desmin (DES) pathogenic variants associated with dilated cardiomyopathy, atrioventricular block and a risk for sudden cardiac death

Fischer, Björn; Dittmann, Sven; Brodehl, Andreas; Unger, Andreas; Stallmeyer, Birgit; Paul, Matthias; Seebohm, Guiscard; Kayser, Anne; Peischard, Stefan; Linke, Wolfgang A.; Milting, Hendrik; Schulze‐Bahr, Eric

doi:10.1016/j.ijcard.2020.12.050

Cited by 18 publications

(9 citation statements)

References 25 publications

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“…DES-deficient mice developed severe cardiomyopathy in combination with skeletal myopathy characterized by fragile myofibrils, severe cardiac fibrosis, cardiomyocyte necrosis and abnormal calcium deposits [108,109]. DES mutations in humans are associated with different skeletal and cardiac myopathies [110][111][112][113][114]. In 2006, Hager and colleagues described for the first time a patient with RCM carrying the mutation DES-p.E245D.…”

Section: Desmin (Des)mentioning

confidence: 99%

Genetic Insights into Primary Restrictive Cardiomyopathy

Brodehl

Gerull²

2022

JCM

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Restrictive cardiomyopathy is a rare cardiac disease causing severe diastolic dysfunction, ventricular stiffness and dilated atria. In consequence, it induces heart failure often with preserved ejection fraction and is associated with a high mortality. Since it is a poor clinical prognosis, patients with restrictive cardiomyopathy frequently require heart transplantation. Genetic as well as non-genetic factors contribute to restrictive cardiomyopathy and a significant portion of cases are of unknown etiology. However, the genetic forms of restrictive cardiomyopathy and the involved molecular pathomechanisms are only partially understood. In this review, we summarize the current knowledge about primary genetic restrictive cardiomyopathy and describe its genetic landscape, which might be of interest for geneticists as well as for cardiologists.

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Section: Desmin (Des)mentioning

confidence: 99%

Genetic Insights into Primary Restrictive Cardiomyopathy

Brodehl

Gerull²

2022

JCM

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“…Des deficient mice developed severe cardiomyopathy in combination with skeletal myopathy characterized by fragile myofibrils, severe cardiac fibrosis, cardiomyocyte necrosis and abnormal calcium deposits [102,103]. DES mutations in humans are associated with different skeletal and cardiac myopathies [104][105][106][107][108]. In 2006, Hager and colleagues described for the first time a patient with RCM carrying the mutation DES-p.E245D.…”

Section: Desmin (Des)mentioning

confidence: 99%

Genetic Insights Into Primary Restrictive Cardiomyopathy

Brodehl¹,

Gerull²

2022

Preprint

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Restrictive cardiomyopathy is a rare cardiac disease causing severe diastolic dysfunction, ventricular stiffness and dilated atria. In consequence, it induces heart failure often with preserved ejection fraction and is associated with a high mortality. Since a poor clinical prognosis, patients with restrictive cardiomyopathy require frequently heart transplantation. Genetic as well as non-genetic factors contribute to restrictive cardiomyopathy and a significant portion of cases remains of unknown etiology. However, the genetic forms of restrictive cardiomyopathy and the involved molecular pathomechanisms are only partially understood. In this review, we summarize the current knowledge about primary genetic restrictive cardiomyopathy and describe its genetic landscape, which might be of interest for geneticists as well as for cardiologists.

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“…Desminopathies manifest clinically as different cardiomyopathies and/or skeletal myopathies [ 1 , 2 ]. The clinical spectrum of desminopathies is wide and heterogenous, and includes different skeletal myopathies and cardiomyopathies such as dilated (DCM) [ 3 , 4 , 5 ], arrhythmogenic (ACM) [ 6 , 7 ], hypertrophic (HCM) [ 8 , 9 ], restrictive (RCM) [ 10 , 11 ] and non-compaction cardiomyopathy (NCCM) [ 12 , 13 ]. Some patients develop a combined cardiac and skeletal muscle phenotype, and even within the same family different phenotypes can be present [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

The N-Terminal Part of the 1A Domain of Desmin Is a Hot Spot Region for Putative Pathogenic DES Mutations Affecting Filament Assembly

Brodehl

Holler

Gummert

et al. 2022

Cells

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Desmin is the major intermediate filament protein of all three muscle cell types, and connects different cell organelles and multi-protein complexes such as the cardiac desmosomes. Several pathogenic mutations in the DES gene cause different skeletal and cardiac myopathies. However, the significance of the majority of DES missense variants is currently unknown, since functional data are lacking. To determine whether desmin missense mutations within the highly conserved 1A coil domain cause a filament assembly defect, we generated a set of variants with unknown significance and systematically analyzed the filament assembly using confocal microscopy in transfected SW-13, H9c2 cells and cardiomyocytes derived from induced pluripotent stem cells. We found that mutations in the N-terminal part of the 1A coil domain affect filament assembly, leading to cytoplasmic desmin aggregation. In contrast, mutant desmin in the C-terminal part of the 1A coil domain forms filamentous structures comparable to wild-type desmin. Our findings suggest that the N-terminal part of the 1A coil domain is a hot spot for pathogenic desmin mutations, which affect desmin filament assembly. This study may have relevance for the genetic counselling of patients carrying variants in the 1A coil domain of the DES gene.

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Functional characterization of novel alpha-helical rod domain desmin (DES) pathogenic variants associated with dilated cardiomyopathy, atrioventricular block and a risk for sudden cardiac death

Cited by 18 publications

References 25 publications

Genetic Insights into Primary Restrictive Cardiomyopathy

Genetic Insights into Primary Restrictive Cardiomyopathy

Genetic Insights Into Primary Restrictive Cardiomyopathy

The N-Terminal Part of the 1A Domain of Desmin Is a Hot Spot Region for Putative Pathogenic DES Mutations Affecting Filament Assembly

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