DSG2 Mutations Contribute to Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy

McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
The American Journal of Human Genetics (Impact Factor: 10.99). 08/2006; 79(1):136-42. DOI: 10.1086/504393
Source: PubMed

ABSTRACT Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is a disorder characterized by fibrofatty replacement of cardiac myocytes that typically manifests in the right ventricle. It is inherited as an autosomal dominant disease with reduced penetrance, although autosomal recessive forms of the disease also occur. We identified four probands with ARVD/C caused by mutations in DSG2, which encodes desmoglein-2, a component of the cardiac desmosome. No association between mutations in this gene and human disease has been reported elsewhere. One of these probands has compound-heterozygous mutations in DSG2, and the remaining three have isolated heterozygous missense mutations, each disrupting known functional components of desmoglein-2. We report that mutations in DSG2 contribute to the development of ARVD/C.

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    ABSTRACT: Background Exercise is associated with age‐related penetrance and arrhythmic risk in carriers of arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C)‐associated desmosomal mutations; however, its role in patients without desmosomal mutations (gene‐elusive) is uncertain. This study investigates whether exercise is (1) associated with onset of gene‐elusive ARVD/C and (2) has a differential impact in desmosomal and gene‐elusive patients. Methods and Results Eighty‐two ARVD/C patients (39 desmosomal, all probands) were interviewed about regular physical activity from age 10. Participation in endurance athletics, duration (hours/year), and intensity (MET‐Hours/year) of exercise prior to clinical presentation were compared between patients with desmosomal and gene‐elusive ARVD/C. All gene‐elusive patients were endurance athletes. Gene‐elusive patients were more likely to be endurance athletes (P<0.001) and had done significantly more intense (MET‐Hrs/year) exercise prior to presentation (P<0.001), particularly among cases presenting < age 25 (P=0.027). Family history was less prevalent among gene‐elusive patients (9% versus 40% desmosomal, P<0.001), suggesting a greater environmental influence. Gene‐elusive patients without family history did considerably more intense exercise than other ARVD/C patients (P=0.004). Gene‐elusive patients who had done the most intense (top quartile MET‐Hrs/year) exercise prior to presentation had a younger age of presentation (P=0.025), greater likelihood of meeting ARVD/C structural Task Force Criteria (100% versus 43%, P=0.02), and shorter survival free from a ventricular arrhythmia in follow‐up (P=0.002). Conclusions Gene‐elusive, non‐familial ARVD/C is associated with very high intensity exercise suggesting exercise has a disproportionate role in the pathogenesis of these cases. As exercise negatively modifies cardiac structure and promotes arrhythmias, exercise restriction is warranted.
    Journal of the American Heart Association 12/2014; 3(6). DOI:10.1161/JAHA.114.001471 · 2.88 Impact Factor
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    ABSTRACT: Understanding the biology of cell surface proteins is important particularly when they are utilized as viral receptors for viral entry. By manipulating the expression of cell surface receptors that have been coopted by viruses, the susceptibility of an individual to virus-induced disease or, alternatively, the effectiveness of viral-based gene therapy can be modified. The most commonly studied vector for gene therapy is adenovirus. The majority of adenovirus types utilize the coxsackievirus and adenovirus receptor (CAR) as a primary receptor to enter cells. Species B adenovirus do not interact with CAR, but instead interact with the cell surface proteins desmoglein-2 (DSG-2) and cluster of differentiation 46 (CD46). These cell surface proteins exhibit varying degrees of alternative mRNA splicing, creating an estimated 20 distinct protein isoforms. It is likely that alternative splice forms have allowed these proteins to optimize their effectiveness in a plethora of niches, including roles as cell adhesion proteins and regulators of the innate immune system. Interestingly, there are soluble isoforms of these viral receptors, which lack the transmembrane domain. These soluble isoforms can potentially bind to the surface of a virus in the extracellular compartment, blocking the ability of the virus to bind to the host cell, reducing viral infectivity. Finally, the diversity of viral receptor isoforms appears to facilitate an assortment of interactions between viral receptor proteins and cytosolic proteins, leading to differential sorting in polarized cells. Using adenoviral receptors as a model system, the purpose of this review is to highlight the role that isoform-specific protein localization plays in the entry of pathogenic viruses from the apical surface of polarized epithelial cells.
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    ABSTRACT: Arrhythmogenic right ventricular cardiomyopathy is an inherited cardiac entity characterized by right ventricular, or biventricular, fibrofatty replacement of myocardium. Structural alterations may lead to sudden cardiac death, mainly in young males during exercise. Autosomal dominant pattern of inheritance is reported in most parts of pathogenic genetic variations identified. Currently, 13 genes have been associated with the disease but nearly 40 % of clinically diagnosed cases remain without a genetic diagnosis. New genetic technologies allow further genetic analysis, generating a significant amount of genetic data in novel genes, which is often classified as of ambiguous significance. We focus on genetic advances of arrhythmogenic right ventricular cardiomyopathy, helping clinicians to interpret and translate genetic data into clinical practice.
    Clinical Research in Cardiology 11/2014; 104(4). DOI:10.1007/s00392-014-0794-z · 4.17 Impact Factor

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