In vitro analysis of arrhythmogenic cardiomyopathy associated desmoglein-2 (DSG2) mutations reveals diverse glycosylation patterns

Debus, Jana Davina; Milting, Hendrik; Kassner, Astrid; Anselmetti, Dario; Gummert, Jan; Gärtner, Anna

doi:10.1016/j.yjmcc.2019.03.014

Cited by 20 publications

(19 citation statements)

References 38 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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. The differentiation of hiPSCs has been previously described [21]. Transfected HT1080 cells were fixed using 4% paraformaldehyde, permeabilized using 0.05% Triton X100, and stained with phalloidin conjugated with Alexa-488.…”

Section: In Vitro Analysis Of Des Variantsmentioning

confidence: 99%

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

Kubánek

Schimerová

Piherová

et al. 2020

JCM

Self Cite

View full text Add to dashboard Cite

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.

show abstract

Section: In Vitro Analysis Of Des Variantsmentioning

confidence: 99%

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

Kubánek

Schimerová

Piherová

et al. 2020

JCM

Self Cite

View full text Add to dashboard Cite

show abstract

“…For example, A1BG, a novel thyroid hormone target, is a plasma glycoprotein of unknown function. Glycoproteins play key roles in in ammatory diseases, are known to be altered in cardiomyopathies and thyroid disorders, and have the potential to be exploited for diagnosis and/or treatment targets [35,36].…”

Section: Discussionmentioning

confidence: 99%

Sex Impacts Cardiac Function and the Proteome Response to Thyroid Hormone in Aged Mice

Zhu¹,

Olson²,

Portman³

et al. 2020

Preprint

View full text Add to dashboard Cite

Background Sex and age have substantial influence on thyroid function. Sex influences the risk and clinical expression of thyroid disorders (TDs), with age a proposed trigger for the development of TDs. Cardiac function is affected by thyroid hormone levels with gender differences. Accordingly, we investigated the proteomic changes involved in sex based cardiac responses to thyroid dysfunction in elderly mice. Methods Aged (18–20 months) male and female C57BL/6 mice were fed diets to create euthyroid, hypothyroid, or hyperthyroid states. Serial echocardiographs were performed to assess heart function. Proteomic changes in cardiac protein profiles were assessed by 2-D DIGE and LC-MS/MS, and a subset confirmed by immunoblotting. Results Serial echocardiographs showed ventricular function remained unchanged regardless of treatment. Heart rate and size increased (hyperthyroid) or decreased (hypothyroid) independent of sex. Pairwise comparison between the six groups identified 55 proteins (≥ 1.5-fold difference and p < 0.1). Compared to same-sex controls 26/55 protein changes were in the female hypothyroid heart, whereas 15/55 protein changes were identified in the male hypothyroid, and male and female hyperthyroid heart. The proteins mapped to oxidative phosphorylation, tissue remodeling and inflammatory response pathways. Conclusion We identified both predicted and novel proteins with gender specific differential expression in response to thyroid hormone status, providing a catalogue of proteins associated with thyroid dysfunction. Pursuit of these proteins and their involvement in cardiac function will expand our understanding of mechanisms involved in sex-based cardiac response to thyroid dysfunction.

show abstract

“…Dsg2 is a major and essential cadherin of the cell-cell contact in cardiac desmosomes (Eshkind, 2002) where it helps to maintain planar coordination of cardiac myocytes. Disruption of adhesive integrity via mutations in the DSG2-gene are regarded to cause severe arrhythmogenic cardiomyopathy (Debus et al, 2019;Krusche et al, 2011;Maron et al, 2006). In contrast, induced deletion of Cx43 in the adult heart did not affect the spatial organization of adherens junction and desmosome in the ID (Gutstein, 2003).…”

Section: Discussionmentioning

confidence: 99%

Repression ofPdzrn3is required for heart maturation and protects against heart failure

Pernot

Jaspard-Vinassa

Abélanet

et al. 2020

Preprint

View full text Add to dashboard Cite

Heart failure is the final common stage of most cardiopathies. Cardiomyocytes connect with others via their extremities by intercalated disk protein complexes. This planar and directional organization of myocytes is crucial for mechanical coupling and anisotropic conduction of the electric signal in the heart. One of the hallmarks of heart failure is alterations in the contact sites between cardiomyocytes. Yet no factor on its own is known to coordinate cardiomyocyte polarized organization. We report enhanced levels of an ubiquitine ligase Pdzrn3 in diseased hypertrophic human and mouse myocardium, which correlates with a loss of cardiomyocyte polarized elongation. We provide evidence that Pdzrn3 has a causative role in heart failure. We found that cardiac Pdzrn3 deficiency protected against heart failure while over expression of Pdzrn3 in mouse cardiomyocytes during the first weeks of life, impaired postnatal cardiomyocyte maturation leading to premature death. Our results reveal a novel signaling pathway that controls a genetic program essential for heart maturation and maintenance of overall geometry, as well as the contractile function of cardiomyocytes, and implicates PDZRN3 as a potential therapeutic target for the prevention of human heart failure.

show abstract

In vitro analysis of arrhythmogenic cardiomyopathy associated desmoglein-2 (DSG2) mutations reveals diverse glycosylation patterns

Cited by 20 publications

References 38 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

Sex Impacts Cardiac Function and the Proteome Response to Thyroid Hormone in Aged Mice

Repression ofPdzrn3is required for heart maturation and protects against heart failure

Contact Info

Product

Resources

About