REVIEW | doi:10.20944/preprints202203.0265.v1
Subject: Medicine And Pharmacology, Cardiac And Cardiovascular Systems Keywords: Restrictive Cardiomyopathy; Cardiomyopathy; Cardiovascular Genetics; Desmin; Troponin; Filamin-C
Online: 18 March 2022 (09:05:21 CET)
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.
ARTICLE | doi:10.20944/preprints202208.0152.v1
Subject: Biology And Life Sciences, Biochemistry And Molecular Biology Keywords: Desmin; Myopathy; Cardiomyopathy; Intermediate Filaments; Cytoskeleton; Myofibrillar Myopathy (MFM); Desminopathy; Desmosomes; Protein Aggregation.
Online: 8 August 2022 (10:48:45 CEST)
Desmin is the major intermediate filament protein of all three muscle cell types and connects different cell organelles and multi-protein complexes like 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 analyzed systematically the filament assembly in transfected SW13 and H9c2 cells using confocal microscopy. We found that mutations in the N-terminal part of the 1A coil domain affect the filament assembly leading to the cytoplasmic desmin aggregation. In contrast, mutant desmin in the C-terminal part of the 1A coil domain form 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 the desmin filament assembly leading in consequence to skeletal and/or cardiac myopathies. This study may have relevance for the genetic counselling of patients carrying variants in the 1A coil domain of the DES gene.