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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.
The cardiovascular system
Published in C. Simon Herrington, Muir's Textbook of Pathology, 2020
Mary N Sheppard, C. Simon Herrington
Arrhythmogenic cardiomyopathy is now regarded as a genetically determined myocardial degenerative disease. It is inherited in an autosomal dominant manner but autosomal recessive forms (e.g. Naxos and Carvajal syndromes caused by mutations in genes encoding plakoglobin [JUP] and desmoplakin [DSP], respectively are recognized). It was the discovery of the genetic basis of Naxos disease that led to the disease being largely due to mutations in desmosomal proteins, which are important in cell-to-cell adhesion, including desmoplakin (DSP), plakophilin-2 (PKP2), desmoglein-2 (DSG2), and desmocolin-2 (DSC2), all of which cause autosomal-dominant forms of AC. Mutations in genes encoding non-desmosomal proteins have also been identified. Most are associated with other cardiomyopathies and arrhythmia syndromes and represent phenotypic overlap. These include the intermediate filament protein desmin (DES), the cardiac sodium channel − Nav 1.5 (SCN5A), lamin A/C (LMNA) on the nuclear membrane, titin (TTN), phospholamban (PLN), and filamin C (FLNC). Pathogenic variants in genes encoding α-T-Catenin (CTNNA3) and N-cadherin (CDH2) have been identified in a small group of AC patients with typical right-predominant disease. The pS358L founder mutation in TMEM43, encoding transmembrane protein 43 is common among French Canadian AC patients. Mutations in transforming growth factor beta-3 (TGFB3) have been described but association with AC remains to be confirmed.
Cardiac and cardiovascular disorders
Published in Angus Clarke, Alex Murray, Julian Sampson, Harper's Practical Genetic Counselling, 2019
In ARVC, the cardiac muscle is replaced by fibrosis and fat, in the right ventricle more than the left. The genes implicated are important for the integrity of cell-cell junctions, such as plakophilin-2 (PKP-2). The condition is characterised by ECG abnormalities, dysrhythmias and sometimes heart failure. Changes may also be seen on cardiac echo. ARVC may lead to sudden death. Specialist cardiac pathology may be required to identify the disorder at examination postmortem. Treatment can be difficult and may require transplantation.
The value of desmosomal plaque-related markers to distinguish squamous cell carcinoma and adenocarcinoma of the lung
Published in Upsala Journal of Medical Sciences, 2020
Inmaculada Galindo, Mercedes Gómez-Morales, Inés Díaz-Cano, Álvaro Andrades, Mercedes Caba-Molina, María Teresa Miranda-León, Pedro Pablo Medina, Joel Martín-Padron, María Esther Fárez-Vidal
The novel markers described here showed a heterogeneous staining of SCC, which was observed in the membranes and cytoplasm of more differentiated cells, marking the intercellular junctions, with staining of nuclei more frequently detected in areas of more immature appearance. In AC samples, focal staining with these novel markers was detected in nucleus and cytoplasm, but never in membrane. In addition to their role in cell adhesion, plakophilins, including PKP1, have been reported to localize to the cytoplasm and nucleus, where they are thought to have several functions that are not completely understood (18). This explains the nuclear and cytoplasmic positivity observed, mainly in SCC in our series. In a few cases and in a few cells, we have also seen occasional nuclear staining for CKT15 and DSG3. Although nuclear localization of CKT15 and DSG3 has not been reported (22,23) and non-specific staining cannot be ruled out, it has been shown that several cytoskeletal proteins, formerly thought to be exclusively cytoplasmic, and including some keratins (keratins 7, 8, 17, and 18), are components of the nuclear matrix, where they may have multiple functions. Some studies of skin and cervical tumours indicated that keratin 17 has a role in the cell cycle and in gene expression regulation (44). These data and the fact that KRT15 and DSG3 are not routinely used in most laboratories prompted our assessment of nuclear staining. Further investigation is warranted to explore the significance of our findings.
Risk stratification for ventricular arrhythmias and sudden cardiac death in arrhythmogenic right ventricular cardiomyopathy: an update
Published in Expert Review of Cardiovascular Therapy, 2019
Julia Cadrin-Tourigny, Laurens P Bosman, Rafik Tadros, Mario Talajic, Lena Rivard, Cynthia A James, Paul Khairy
The notion of a ‘concealed phase’ of ARVC with arrhythmia occurring before any phenotypic manifestation has been proposed. This concept is also supported by the experimental evidence of the relationships between desmosomes and electrical components [18]. The clinical literature suggests that phenotypic expression is usually a pre-requisite for VA but with exceptions. In one study in which 116 mutation carriers were followed for 8.5 years, only one had an arrhythmic outcome (i.e., SCD) before ARVC was diagnosed. The autopsy of this desmoplakin mutation carrier revealed a scar in the LV, thereby suggesting that the diagnostic tests lacked sensitivity as opposed to a true event before any phenotypic expression [10]. Recently, a case series reported 4 patients with a pathogenic plakophilin 2 mutation and SCD in the context of structurally normal hearts [28]. These results support the concept that, although rare and probably under-recognized, arrhythmic events in the concealed phase of the disease do occur.
Epithelial maturity influences EPEC-induced desmosomal alterations
Published in Gut Microbes, 2019
Jennifer Lising Roxas, Gayatri Vedantam, V.K. Viswanathan
Reflecting this varied composition and tissue topology, desmosomal perturbations have distinct impacts in different tissues. Loss of desmosomal contacts in the skin manifests as blisters due to acantholysis or separation of keratinocytes, as observed in patients suffering from the auto-immune conditions pemphigus vulgaris and pemphigus foliaceus, or from Staphylococcus aureus-induced bullous impetigo.7 Desmosomes are critical in heart morphogenesis and function. Plakophilin-2- or plakoglobin-null mouse embryos die during mid-gestation due to rupturing of cardiac ventricles.8–10 In humans, mutations in desmosome-related genes are strongly linked to arrhythmogenic cardiomyopathy, which is characterized by fibrofatty replacement of the heart muscle, right ventricular arrhythmias and sudden death.4,11–14 In the intestine, desmosomal disruptions could weaken the monolayer and lead to breaches in the epithelial barrier and consequent transfer of microbial components into the underlying tissue. As a virulence strategy, some enteric pathogens, including Entamoeba histolytica, dismantle desmosomes to invade the host.15