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.

@article{Fischer2020FunctionalCO,
  title={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.},
  author={Bj{\"o}rn Fischer and Sven Dittmann and Andreas Brodehl and Andreas Unger and Birgit Stallmeyer and Matthias Paul and Guiscard Seebohm and Anne Kayser and Stefan Peischard and Wolfgang A. Linke and Hendrik Milting and Eric Schulze-Bahr},
  journal={International journal of cardiology},
  year={2020}
}
4 Citations
The Desmin Mutation DES-c.735G>C Causes Severe Restrictive Cardiomyopathy by Inducing In-Frame Skipping of Exon-3
TLDR
It is shown that DES-c.735G>C causes a splicing defect leading to exon-3 skipping of the DES gene, which can be classified as a pathogenic mutation associated with RCM and atrial fibrillation.
Genetic Insights into Primary Restrictive Cardiomyopathy
TLDR
The current knowledge about primary genetic restrictive cardiomyopathy is summarized and its genetic landscape is described, which might be of interest for geneticists as well as for cardiologists.

References

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Noncompaction cardiomyopathy is caused by a novel in‐frame desmin (DES) deletion mutation within the 1A coiled‐coil rod segment leading to a severe filament assembly defect
TLDR
The genetic analysis revealed a novel small in‐frame deletion within the DES gene, p.Q113_L115del, affecting the α‐helical rod domain, classified as a pathogenic mutation associated with dilated cardiomyopathy with prominent LVHT.
Novel Desmin Mutation p.Glu401Asp Impairs Filament Formation, Disrupts Cell Membrane Integrity, and Causes Severe Arrhythmogenic Left Ventricular Cardiomyopathy/Dysplasia
TLDR
The novel DES-p.Glu401Asp mutation causes predominant inherited left ventricular arrhythmogenic cardiomyopathy/dysplasia with a high incidence of adverse clinical events in the absence of skeletal myopathy or conduction system disorders.
The Novel Desmin Mutant p.A120D Impairs Filament Formation, Prevents Intercalated Disk Localization, and Causes Sudden Cardiac Death
TLDR
Two novel variants of the intermediate filament protein desmin, encoded by the gene DES, are identified with a broad spectrum of cardiomyopathies with a striking frequency of arrhythmias and sudden cardiac deaths and model variants of codon 120 indicated that ionic interactions contribute to this filament formation defect.
Prevalence of Desmin Mutations in Dilated Cardiomyopathy
TLDR
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.
Restrictive Cardiomyopathy is Caused by a Novel Homozygous Desmin (DES) Mutation p.Y122H Leading to a Severe Filament Assembly Defect
TLDR
A small Iranian family, where the index patient received a diagnosis of restrictive cardiomyopathy (RCM) in combination with atrioventricular (AV) block, is presented, where a novel homozygous missense mutation in the DES gene (c.364T > C; p.Y122H) is revealed, which is absent in human population databases.
De novo desmin-mutation N116S is associated with arrhythmogenic right ventricular cardiomyopathy.
TLDR
The gene coding for desmin appears to be a novel ARVC gene, which should be included in molecular genetic screening of ARVC patients, and is found in segment 1A of the desmin rod domain.
The toxic effect of R350P mutant desmin in striated muscle of man and mouse
TLDR
It is demonstrated that the missense-mutant desmin inflicts changes of the subcellular localization and turnover of desmin itself and of direct desmin-binding partners, which unveil a novel principle of pathogenesis, in which not the presence of protein aggregates, but disruption of the extrasarcomeric intermediate filament network leads to increased mechanical vulnerability of muscle fibers.
Intermediate filament diseases: desminopathy.
TLDR
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.
Desmin myopathy, a skeletal myopathy with cardiomyopathy caused by mutations in the desmin gene.
TLDR
The mutant desmin interferes with the normal assembly of intermediate filaments, resulting in fragility of the myofibrillar or desmin-related myopathy and severe dysfunction of skeletal and cardiac muscles.
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