Restrictive Cardiomyopathy is Caused by a Novel Homozygous Desmin (DES) Mutation p.Y122H Leading to a Severe Filament Assembly Defect

Brodehl, Andreas; Hakimi, Pour; Stanasiuk, Caroline; Ratnavadivel, Sandra; Hendig, Doris; Gaertner, Andrea; Gerull, Brenda; Gummert, Jan; Paluszkiewicz, Lech

doi:10.3390/genes10110918

Cited by 56 publications

(63 citation statements)

References 44 publications

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“…Desmin encoding parts of all plasmids were verified by Sanger sequencing (Macrogen, Amsterdam, Netherlands). The plasmid pmRuby-N1-DES and pmRuby-N1-DES-p.(Y122C) have been previously described [19,20]. Previously reported variant DES-p.(Y122C) was used as a positive control forming abnormal cytoplasmic aggregates [20].…”

Section: In Vitro Analysis Of Des Variantsmentioning

confidence: 99%

“…The plasmid pmRuby-N1-DES and pmRuby-N1-DES-p.(Y122C) have been previously described [19,20]. Previously reported variant DES-p.(Y122C) was used as a positive control forming abnormal cytoplasmic aggregates [20]. HT1080 cells, which do not express endogenous desmin and cardiomyocytes derived from human induced pluripotent stem cells (iPSC) (NP00040-8) were transfected using Lipofectamin 3000 (ThermoFisher Scientific) or nucleofection using the 4D Nucleofector (Lonza, Cologne, Germany) in combination with the P3 Primary Cell 4D Nucleofector Kit according to the manufacturer's instructions.…”

Section: In Vitro Analysis Of Des Variantsmentioning

confidence: 99%

“…* p < 0.05 and ** p < 0.01. The variant DES-p.(Y122C) was used as a positive control forming abnormal cytoplasmic aggregates [20].…”

Section: Phenotypes Of Desminopathymentioning

confidence: 99%

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Desminopathy: Novel Desmin Variants, a New Cardiac Phenotype, and Further Evidence for Secondary Mitochondrial Dysfunction

Kubánek

Schimerová

Piherová

et al. 2020

JCM

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Background: The pleomorphic clinical presentation makes the diagnosis of desminopathy difficult. We aimed to describe the prevalence, phenotypic expression, and mitochondrial function of individuals with putative disease-causing desmin (DES) variants identified in patients with an unexplained etiology of cardiomyopathy. Methods: A total of 327 Czech patients underwent whole exome sequencing and detailed phenotyping in probands harboring DES variants. Results: Rare, conserved, and possibly pathogenic DES variants were identified in six (1.8%) probands. Two DES variants previously classified as variants of uncertain significance (p.(K43E), p.(S57L)), one novel DES variant (p.(A210D)), and two known pathogenic DES variants (p.(R406W), p.(R454W)) were associated with characteristic desmin-immunoreactive aggregates in myocardial and/or skeletal biopsy samples. The individual with the novel DES variant p.(Q364H) had a decreased myocardial expression of desmin with absent desmin aggregates in myocardial/skeletal muscle biopsy and presented with familial left ventricular non-compaction cardiomyopathy (LVNC), a relatively novel phenotype associated with desminopathy. An assessment of the mitochondrial function in four probands heterozygous for a disease-causing DES variant confirmed a decreased metabolic capacity of mitochondrial respiratory chain complexes in myocardial/skeletal muscle specimens, which was in case of myocardial succinate respiration more profound than in other cardiomyopathies. Conclusions: The presence of desminopathy should also be considered in individuals with LVNC, and in the differential diagnosis of mitochondrial diseases.

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Section: In Vitro Analysis Of Des Variantsmentioning

confidence: 99%

Section: In Vitro Analysis Of Des Variantsmentioning

confidence: 99%

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Desminopathy: Novel Desmin Variants, a New Cardiac Phenotype, and Further Evidence for Secondary Mitochondrial Dysfunction

Kubánek

Schimerová

Piherová

et al. 2020

JCM

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“…Restrictive cardiomyopathy can have many causes: metabolic disorders like diabetes, genetically caused storage diseases like amyloidosis, and point mutations of sarcomeric proteins inherited in a dominant autosomal manner (for review see also Muchtar et al 2017 [7]). Point mutations have been identified in a number of different sarcomeric components such as the heavy myosin chain of β-myosin (MYH7), myosin binding protein C (MYBPC3), and the troponin subunits cTnC (TNNC1), cTnI (TNNI3) and cTnT (TNNT2) as well as in cytoskeletal components like filamin (FLNC), αB-crystallin (CRYAB), and desmin (DES) [3,[8][9][10][11][12][13]. A number of RCM causing point mutations were identified in cTnI (TNNI3) that are clustered in its C-terminal region [4,[14][15][16][17].…”

Section: Introductionmentioning

confidence: 99%

Infantile restrictive cardiomyopathy: cTnI-R170G/W impair the interplay of sarcomeric proteins and the integrity of thin filaments

et al. 2020

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TNNI3 encoding cTnI, the inhibitory subunit of the troponin complex, is the main target for mutations leading to restrictive cardiomyopathy (RCM). Here we investigate two cTnI-R170G/W amino acid replacements, identified in infantile RCM patients, which are located in the regulatory C-terminus of cTnI. The C-terminus is thought to modulate the function of the inhibitory region of cTnI. Both cTnI-R170G/W strongly enhanced the Ca 2+-sensitivity of skinned fibres, as is typical for RCM-mutations. Both mutants strongly enhanced the affinity of troponin (cTn) to tropomyosin compared to wildtype cTn, whereas binding to actin was either strengthened (R170G) or weakened (R170W). Furthermore, the stability of reconstituted thin filaments was reduced as revealed by electron microscopy. Filaments containing R170G/W appeared wavy and showed breaks. Decoration of filaments with myosin subfragment S1 was normal in the presence of R170W, but was irregular with R170G. Surprisingly, both mutants did not affect the Ca 2+-dependent activation of reconstituted cardiac thin filaments. In the presence of the N-terminal fragment of cardiac myosin binding protein C (cMyBPC-C0C2) cooperativity of thin filament activation was increased only when the filaments contained wildtype cTn. No effect was observed in the presence of cTn containing R170G/W. cMyBPC-C0C2 significantly reduced binding of wildtype troponin to actin/tropomyosin, but not of both mutant cTn. Moreover, we found a direct troponin/cMyBPC-C0C2 interaction using microscale thermophoresis and identified cTnI and cTnT, but not cTnC as binding partners for cMyBPC-C0C2. Only cTn containing cTnI-R170G showed a reduced affinity towards cMyBPC-C0C2. Our results suggest that the RCM cTnI variants R170G/W

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“…Although desmin is not directly a Z-band protein, it forms cytoplasmic IF and is involved in connection of the Z-bands ( Hijikata et al, 1999 ), desmosomes ( Choi et al, 2002 ), mitochondria ( Capetanaki, 2002 ), and also the nuclei ( Heffler et al, 2020 ) in cardiomyocytes. Mutations in DES cause different skeletal and cardiac myopathies, including DCM ( Li et al, 1999 ; Brodehl et al, 2016a ), HCM ( Harada et al, 2018 ), RCM ( Brodehl et al, 2019c ), LVNC ( Marakhonov et al, 2019 ; Kubanek et al, 2020 ), and also ACM ( Klauke et al, 2010 ; Bermudez-Jimenez et al, 2018 ). Desmin consists of a central α-helical rod domain flanked by nonhelical head and tail domains.…”

Section: Animal Models For Acm Associated With Mutations In Nondesmosmentioning

confidence: 99%

Genetic Animal Models for Arrhythmogenic Cardiomyopathy

Gerull

Brodehl

2020

Front. Physiol.

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Arrhythmogenic cardiomyopathy has been clinically defined since the 1980s and causes right or biventricular cardiomyopathy associated with ventricular arrhythmia. Although it is a rare cardiac disease, it is responsible for a significant proportion of sudden cardiac deaths, especially in athletes. The majority of patients with arrhythmogenic cardiomyopathy carry one or more genetic variants in desmosomal genes. In the 1990s, several knockout mouse models of genes encoding for desmosomal proteins involved in cell–cell adhesion revealed for the first time embryonic lethality due to cardiac defects. Influenced by these initial discoveries in mice, arrhythmogenic cardiomyopathy received an increasing interest in human cardiovascular genetics, leading to the discovery of mutations initially in desmosomal genes and later on in more than 25 different genes. Of note, even in the clinic, routine genetic diagnostics are important for risk prediction of patients and their relatives with arrhythmogenic cardiomyopathy. Based on improvements in genetic animal engineering, different transgenic, knock-in, or cardiac-specific knockout animal models for desmosomal and nondesmosomal proteins have been generated, leading to important discoveries in this field. Here, we present an overview about the existing animal models of arrhythmogenic cardiomyopathy with a focus on the underlying pathomechanism and its importance for understanding of this disease. Prospectively, novel mechanistic insights gained from the whole animal, organ, tissue, cellular, and molecular levels will lead to the development of efficient personalized therapies for treatment of arrhythmogenic cardiomyopathy.

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Restrictive Cardiomyopathy is Caused by a Novel Homozygous Desmin (DES) Mutation p.Y122H Leading to a Severe Filament Assembly Defect

Cited by 56 publications

References 44 publications

Desminopathy: Novel Desmin Variants, a New Cardiac Phenotype, and Further Evidence for Secondary Mitochondrial Dysfunction

Desminopathy: Novel Desmin Variants, a New Cardiac Phenotype, and Further Evidence for Secondary Mitochondrial Dysfunction

Infantile restrictive cardiomyopathy: cTnI-R170G/W impair the interplay of sarcomeric proteins and the integrity of thin filaments

Genetic Animal Models for Arrhythmogenic Cardiomyopathy

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