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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.
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
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.
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
The second architectural feature we quantified from the dSTORM images was desmosome length. There was a cell line-dependent difference in how the desmosome length changed with maturation: the length increased as E-cadherin was sorted out only in MDCK cells. Changes in the length are not unexpected, and an increase in desmosome length has also been observed in plakophilin 1 overexpression-induced hyperadhesion for example.31 However, it is not known how desmosome length is regulated, and cell-type specific differences are possible. When interpreting our data, it is important to note that the doubling time of MDCK cells (~30 h) is approximately half that of NHEK or HUC cells (~60-115 h).32–34 It is conceivable that the increase in the plaque length is a universal feature, which is not correlated with E-cadherin exclusion or adhesion but our timeline was not long enough to capture this in the NHEK and HUC cell lines.
Skin proteomics – analysis of the extracellular matrix in health and disease
Published in Expert Review of Proteomics, 2020
Jörn Dengjel, Leena Bruckner-Tuderman, Alexander Nyström
As protein phosphorylation is a major determinant of protein activation and regulator of protein–protein interactions its analysis has received a lot of attention. MS-based proteomic approaches are the method of choice to study alterations in the phosphorylation status of proteins giving rise to the research field of phosphoproteomics [129]. As for expression proteomic experiments, initial studies addressing protein phosphorylation in skin cells were coupled to 2D-PAGE [130]. Especially the effect of irradiation on skin cells was analyzed by phosphoproteomic approaches, highlighting that skin fibroblasts respond differentially to low and high doses of ionizing radiation [131,132]. Later, phosphoproteomic approaches were coupled with elegant mechanistic studies. E.g. in mouse skin and mouse keratinocytes Polo-like Kinase 1 (Plk1) was identified to regulate keratinocyte planar cell polarity by phosphorylating the protein Celsr1, regulating its endosomal recruitment during mitosis [133]. Specific phosphorylation events were also shown to be important for skin cell differentiation: the kinase CSNK1a1 was shown to be important for keratinocyte progenitor maintenance by phosphorylating protein arginine methyltransferase 1 (PRMT1) [134]; receptor-interacting serine-threonine kinase 4 (Ripk4) was identified to phosphorylate the desmosome component plakophilin-1 (Pkp1) in mouse keratinocyte differentiation [135]. Absence of either of the two proteins led to enhanced epidermal carcinogenesis.
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
Desmosomes are cell structures specialized for focal cell-to-cell adhesion that are localized in randomly arranged spots on the lateral sides of plasma membranes. They play an important role in providing strength to tissues under mechanical stress, such as the cardiac muscle and epidermis. Besides the constitutive desmosomal plaque proteins desmoplakin and plakoglobin, at least one of the three classical members of the plakophilin (PKP) family is required to form functional desmosomes (12–14). PKP1 is a major desmosomal plaque component that recruits intermediate filaments to sites of cell–cell contact via interaction with desmoplakin. PKPs regulate cellular processes, including protein synthesis and cell growth, proliferation, and migration, and they have been implicated in tumour development (15–21).