Article

Role of genetic testing in arrhythmogenic right ventricular cardiomyopathy/dysplasia

Institut de Cardiologie de Montréal, Montréal, Québec, Canada.
Clinical Genetics (Impact Factor: 3.93). 10/2009; 77(1):37-48. DOI: 10.1111/j.1399-0004.2009.01282.x
Source: PubMed

ABSTRACT

Barahona-Dussault C, Benito B, Campuzano O, Iglesias A, Leung TL, Robb L, Talajic M, Brugada R. Role of genetic testing in arrhythmogenic right ventricular cardiomyopathy/dysplasia.
In a cohort of patients with confirmed or suspected arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D), genetic testing is useful in confirming the diagnosis, particularly in individuals who do not completely fulfil Task Force criteria for the disease, thereby also enabling the adoption of preventive measures in family members. Due to the high percentage of novel mutations that are expected to be identified in ARVC/D, the use of genetic screening technology based on the identification of known mutations seems to have very restricted value. Our results support that the presence of certain genetic variations could play a role in the final phenotype of patients with ARVC/D, where single and compound mutation carriers would have more symptomatic forms of the disease and the polymorphism P366L could be associated to a more benign phenotype.

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    • "The EC1 domain of DSC2 exhibits potentially destabilising ARVC-linked mutations including G150A, R203C, R203H, G220R, and I231T [64] [68] [69] [89]. ARVC-linked pathogenic mutations in the EC2 domain of DSC2 include T275M, P292S, T340A, I342V, I345T, and D350Y, with the latter mutation removing a Ca 2+ coordinating group that rigidifies the linkage to EC3 [52] [54] [64] [89]. The E102K and I345T mutant DSC2 proteins delocalize from the plasma membrane to the cytosol [90], inferring trafficking defects, while the R203C and T275M mutants show impaired proteolytic processing [64]. "

    Full-text · Dataset · Oct 2013
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    • "The EC1 domain of DSC2 exhibits potentially destabilising ARVC-linked mutations including G150A, R203C, R203H, G220R, and I231T [64] [68] [69] [89]. ARVC-linked pathogenic mutations in the EC2 domain of DSC2 include T275M, P292S, T340A, I342V, I345T, and D350Y, with the latter mutation removing a Ca 2+ coordinating group that rigidifies the linkage to EC3 [52] [54] [64] [89]. The E102K and I345T mutant DSC2 proteins delocalize from the plasma membrane to the cytosol [90], inferring trafficking defects, while the R203C and T275M mutants show impaired proteolytic processing [64]. "
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    ABSTRACT: Desmosomes are dynamic junctions between cells that maintain the structural integrity of skin and heart tissues by withstanding shear forces. Mutations in component genes cause life threatening conditions including arrhythmogenic right ventricular cardiomyopathy, and desmosomal proteins are targeted by pathogenic autoantibodies in skin blistering diseases such as pemphigus. Here we review a set of newly discovered pathogenic alterations, and discuss the structural repercussions of debilitating mutations on desmosomal proteins. The architectures of native desmosomal assemblies have been visualised by cryo-electron microscopy and cryo-electron tomography, and the network of protein domain interactions is becoming apparent. Plakophilin and desmoplakin mutations have been discovered to alter binding interfaces, structures and stabilities of folded domains which have been resolved by X-ray crystallography and NMR spectroscopy. The flexibility within desmoplakin has been revealed by small angle X-ray scattering and fluorescence assays, explaining how mechanical stresses are accommodated. These studies have shown that the structural and functional consequences of desmosomal mutations can now begin to be understood at multiple levels of spatial and temporal resolution. This review discusses the recent structural insights and raises the possibility of using modelling for mechanism-based diagnosis of how deleterious mutations alter the integrity of solid tissues.
    Full-text · Article · Aug 2013 · Journal of Molecular Biology
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    • "A > T coding for E1833V) was identified in the index patient (35.1). A recent study has suggested a frequency of 1.5% for this polymorphism.25 In the same family, the DSC2 R203C mutation was also found in Individual 35.3, who was negative for the DSP E1833V variant. "
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    ABSTRACT: Recent immunohistochemical studies observed the loss of plakoglobin (PG) from the intercalated disc (ID) as a hallmark of arrhythmogenic right ventricular cardiomyopathy (ARVC), suggesting a final common pathway for this disease. However, the underlying molecular processes are poorly understood. We have identified novel mutations in the desmosomal cadherin desmocollin 2 (DSC2 R203C, L229X, T275M, and G371fsX378). The two missense mutations (DSC2 R203C and T275M) have been functionally characterized, together with a previously reported frameshift variant (DSC2 A897fsX900), to examine their pathogenic potential towards PG's functions at the ID. The three mutant proteins were transiently expressed in various cellular systems and assayed for expression, processing, localization, and binding to other desmosomal components in comparison to wild-type DSC2a protein. The two missense mutations showed defects in proteolytic cleavage, a process which is required for the functional activation of mature cadherins. In both cases, this is thought to cause a reduction of functional DSC2 at the desmosomes in cardiac cells. In contrast, the frameshift variant was incorporated into cardiac desmosomes; however, it showed reduced binding to PG. Despite different modes of action, for all three variants, the reduced ability to provide a ligand for PG at the desmosomes was observed. This is in agreement with the reduced intensity of PG at these structures observed in ARVC patients.
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