Explore chapters and articles related to this topic
Cardiac Hypertrophy, Heart Failure and Cardiomyopathy
Published in Mary N. Sheppard, Practical Cardiovascular Pathology, 2022
The use of EMB for the diagnosis is controversial in view of the location of the pathological features in this condition. Its use generally in diagnosis of cardiomyopathies is limited. The presence of adipose tissue alone is insufficient since it is a normal component of the right ventricle so the amount of fibrosis is more important but is nonspecific. Image-guided biopsies may be more informative but more for the elimination of other causes. Myocarditis and sarcoid may clinically mimic ACM, and EMB is useful in these situations. The use of immunocytochemistry showing a marked reduction in immunoreactive signal levels for plakoglobin remains nonspecific and has not proven useful.
Companion Animals Models of Human Disease
Published in Rebecca A. Krimins, Learning from Disease in Pets, 2020
Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with a mutation in the striatin gene in Boxer dogs(39). The disease appeared to be autosomal dominant with incomplete and age-dependent penetrance. A genome wide association study (GWAS) identified a region CFA17 in the Boxer as being highly associated. Evaluation of the underlying gene striatin, calmodulin binding protein (STRN), revealed an 8-bp deletion in the 3′ untranslated region. Both homozygotes and heterozygotes were identified, but the dogs that were homozygous for the deletion had a more severe form of the disease. A subsequent study identified the second clinical form of myocardial disease seen in Boxers, dilated cardiomyopathy, as being caused by a deletion in the same gene in at least some families. The encoded protein is believed to serve as a scaffold that functions in a calcium-dependent manner in both signaling and trafficking. The authors made the novel observation that STRN protein colocalizes with the desmosomal proteins plakophilin-2, plakoglobin, and desmoplakin. All are proteins that are involved in the human forms of ventricular cardiomyopathy. STRN now becomes a superb candidate gene for unexplained familial and sporadic forms of the human disease.
Arrhythmogenic Right Ventricular Cardiomyopathy
Published in Andrea Natale, Oussama M. Wazni, Kalyanam Shivkumar, Francis E. Marchlinski, Handbook of Cardiac Electrophysiology, 2020
Daniele Muser, Pasquale Santangeli
ARVC is a genetically determined cardiomyopathy with heterogeneous inheritance and clinical phenotype with variable penetrance and clinical severity of the disease among family trees. In up to 50% of the cases, a definite causal gene mutation cannot be found while desmosomal gene mutations are responsible for the disease in the 70% of cases with a positive genetic test.9 The first mutations causing the disease were found in 2000 in genes encoding for the desmosomal proteins plakoglobin and desmoplakin among patients with autosomal recessive Naxos and Carvajal cardiocutaneous syndromes, respectively.10–12 Both present woolly hair, keratoderma and arrhythmogenic cardiomyopathy with a higher incidence of LV involvement in the second one. Other desmosomal genes encoding for plakophilin, desmoglein, and desmocollin have also been discovered and have been associated to both autosomal recessive and dominant forms.13–15 In a lower proportion of cases, genes encoding for other non-desmosomal proteins like the ryanodine receptor and the transforming growth factor-β3 have been found.16,17 Mutations in the genes encoding for titin, lamin A/C and phospholamban have also been described and typically lead to arrhythmogenic syndromes characterized by a dilated cardiomyopathy phenotype overlapping with the classical ARVC phenotype.18–20
Naxos disease – a narrative review
Published in Expert Review of Cardiovascular Therapy, 2020
Marianna Leopoulou, Gustav Mattsson, Jo Ann LeQuang, Joseph V Pergolizzi, Giustino Varrassi, Marita Wallhagen, Peter Magnusson
In Naxos disease, there is a loss of healthy myocardium in the right ventricle, especially in the subepicardial and mediomural layers, as it becomes replaced by fibrofatty tissue [12]. The gene associated with the disease was first identified on chromosome 17 in position q21 [4]. Since then, genetic investigations have concluded that a mutation, Pk2157del2TG, in the gene truncating the C-terminal of the protein plakoglobin, is the causative genetic mutation associated with Naxos disease [6,9]. Furthermore, a homozygous 2-bp deletion (c.2157delTG) in the plakoglobin gene has been associated with the disease [8]. Plakoglobin (γ-catenin) is a protein involved in myocardial cell adhesion [4]. In more detail, it constitutes a component of both the desmosomes (where it connects with the intermediate filaments of desmin) and of the adherence junctions (where it is connected to the actin skeleton); both are involved in mechanical contraction and also act as signaling molecules [9,30]. In addition, plakoglobin is homologous with keratin filaments. As a result, the mutation of the plakoglobin protein disrupts the desmosomal cutaneous links in which the keratin attaches, resulting in hyperplasia of the keratin layer following mechanical pressure [4]. Defective cell adhesion caused by plakoglobin mutations also reduces connexin-43 levels, a major gap-junction protein; this, in turn, causes myocardial gap junction remodeling, which contributes to the arrhythmogenic substrate of Naxos disease [29].
Circulating tumor cell clusters: Insights into tumour dissemination and metastasis
Published in Expert Review of Molecular Diagnostics, 2020
Sayuri Herath, Sajad Razavi Bazaz, James Monkman, Majid Ebrahimi Warkiani, Derek Richard, Ken O’Byrne, Arutha Kulasinghe
CTCs can exist as single cells or clusters. Aggregation of two or more CTCs through intracellular junctions are known as CTC Clusters [3–6]. From a series of mouse model experiments, Aceto et al. (2014) revealed that CTC clusters are derived from primary tumor cells, denoting an oligoclonal origin [7]. A recent study in breast cancer indicated that plakoglobin, a major cytoplasmic component of both desmosomes and adherens junctions, works as a key factor for tumor cell clustering [8]. The study emphasized that downregulation of plakoglobin leads to a reduction of CTC cluster formation and lowering of the metastatic capacity [7]. More recently, two studies discovered that tight junction proteins claudin 3 and claudin 4 play a significant role in cluster formation [7,9]. The studies revealed that intracellular junctions have a more profound effect than the cell to cell interactions for the formation of metastasis. It has also been shown that DNA methylation dynamics significantly impact on CTC cluster formation which enhances stemness and metastatic seeding ability. Aggregation of CTCs leads to hypomethylation of binding sites for stemness and proliferation-associated transcription factor and the disruption of multicellular structures in CTC clusters causes re-methylation of transcription factor binding sites and suppression of metastatic dissemination [9]. A summary of CTC clusters has been detailed in Table 1.
Desmosomes undergo dynamic architectural changes during assembly and maturation
Published in Tissue Barriers, 2022
Reena R. Beggs, Tejeshwar C. Rao, William F. Dean, Andrew P. Kowalczyk, Alexa L. Mattheyses
There are several possible factors that could be underlying the decrease in the plaque-to-plaque distance of the desmoplakin rod/C-terminal junction such as an isoform switch, a decrease of intercellular space, an overall movement of desmoplakin, or rearrangement of desmoplakin within the desmosomal plaque (Figure 2a). The rod/C-terminal domain antibody we utilized for dSTORM was raised against a region specific to desmoplakin I. Therefore, we do not consider a shift in desmoplakin isoforms to be an underlying mechanism for our results. Next, to address if other plaque proteins also underwent an architectural rearrangement, we performed a parallel analysis on plakoglobin, another essential desmosomal component (Figure 2b). There was no statistically significant change in the plakoglobin plaque-to-plaque distance across all time points (at 3 h, 86 ± 38 nm) (Figure 2b, c). The plakoglobin plaque length increased during maturation between 3 and 12 h (156 ± 53 to 256 ± 73 nm) (Figure 2b, d). Plakoglobin is located proximal to the plasma membrane in the outer dense plaque. Therefore, our results suggest that there is no change in the width of the extracellular space during maturation. Finally, to scrutinize if there was a movement of the entire desmoplakin protein or only certain domains within the plaque, we imaged cells labeled with an antibody to the desmoplakin N-terminal domain. There was no significant difference in the plaque-to-plaque distance between 3 and 12 h although there was an increase in the plaque length (Figure 2e-f). Together, these data indicate a domain-specific change in desmoplakin organization during desmosome assembly.