Arrhythmogenic right ventricular cardiomyopathy is a familial cardiomyopathy characterized by progressive right (and sometimes left) ventricular and interventricular myocardial atrophy and fibrofatty replacement.1-4 Clinically, ARVC is characterized by ventricular tachyarrhythmias of right ventricular origin that can lead to sudden cardiac death, and in some individuals, progression to myocardial dysfunction and heart failure.5 Arrhythmogenic right ventricular cardiomyopathy is a common cause of heart disease in Boxers, and affected dogs may develop syncope or signs associated with congestive heart failure or die of sudden cardiac death without overt clinical signs.2 The diagnosis of ARVC has also been made in other species, including cats and humans.1,4 The familial aspects of ARVC have been studied most extensively in humans; it has been estimated that ARVC accounts for as many as 5% of sudden cardiac deaths among young adults in the United States and has a prevalence of 1 in 5,000 persons (with some geographic variation).5,6
Because 4 of the reported genes that contain causative mutations encode desmosomal proteins, it has been proposed that ARVC is a disease of the desmosome.8 Desmosomes are multiprotein complexes located in the cell membrane that provide both structural and functional integrity to adjacent cells as well as a link between the plasma membrane to the cytoskeleton.3,9 Causative mutations have been identified in the 3 genes that encode desmoplakin, plakoglobin, and plakophilin-2; these desmosomal proteins are responsible for the mechanical coupling of the myocytes and provide a continuous cell-to-cell connection to the sarcomeric actin and the intermediate filaments.10 A fourth gene containing causative mutations is desmoglein-2. Desmogleins form one of the essential transmembrane components of desmosomes.11 The discovery of causative mutations for ARVC within genes encoding desmosomal proteins has led to the proposal that ARVC is a result of defective cell-adhesion proteins in the desmosome of cardiomyocytes.10 The lack of normal protein or incorporation of mutant protein into the cardiac desmosome may provoke detachment of myocytes at the intercalated disks, especially under conditions of mechanical stress.10 This impaired cell adhesion could lead to accelerated apoptosis of myocardial cells, resulting in the underlying pathogenic mechanisms.7,10 Causative mutations for ARVC have also been identified in 2 genes that encode the nondesmosomal proteins TGF-β3 and the cardiac ryanodine receptor, respectively.12,13 Interestingly, although TGF-β3 does not encode a desmosomal protein, it is involved in modulation of cell adhesion.
Similarities between the human and canine forms of ARVC include myocardial atrophy and fibrofatty replacement predominantly in the right ventricle, ventricular tachyarrhythmias of right ventricular origin, and a clinical syndrome that can include sudden cardiac death or myocardial dysfunction, as well as an autosomal dominant mode of inheritance.2,14-17 By use of linkage analysis, our group has determined that the cardiac ryanodine receptor is not linked with ARVC in Boxers.18 The purpose of the study reported here was to sequence the exonic and splice site regions of the 4 desmosomal genes associated with the human form of familial ARVC in Boxers with ARVC and identify a causative mutation. Our hypothesis was that mutations in the desmosomal genes would be causative for ARVC in Boxers.
Arrhythmogenic right ventricular cardiomyopathy
Transforming growth factor–β3
Fermentas, Hanover, Md.
ExoSapIt, GE Healthcare Bio-Sciences Corp, Piscataway, NJ.
ABI Prism 377 Sequencer, Applied Biosystems, Foster City, Calif.
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Pilichou K, Nava A, Basso C, et al. Mutations in desmoglein-2 gene are associated with arrhythmogenic right ventricular cardiomyopathy. Circulation 2006;113:1171–1179.
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Beffagna G, Occhi G, Nava A, et al. Regulatory mutations in transforming growth factor-β3 gene cause arrhythmogenic right ventriuclar cardiomyopathy type 1. Cardiovasc Res 2005;65:366–373.
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Meurs KM, Lacombe V, Dryburgh K, et al. Differential expression of the cardiac ryanodine receptor in normal and arrhythmogenic right ventricular cardiomyopathy canine hearts. Hum Genet 2006;120:111–118.
Spier AW, Meurs KM, Muir WW, et al. Correlation of QT dispersion with indices used to evaluate the severity of familial ventricular arrhythmias in Boxers. Am J Vet Res 2001;62:1481–1485.
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Kaplan SR, Gard JJ, Protonotarios N, et al. Remodeling of myocyte gap junctions in arrhythmogenic right ventricular cardiomyopathy due to a deletion in plakoglobin (Naxos disease). Heart Rhythm 2004;1:3–11.
Rampazzo A, Nava A, Malacrida S, et al. Mutation in human desmoplakin domain binding to plakoglobulin causes a dominant form of arrhythmogenic right ventricular cardiomyopathy. Am J Hum Genet 2006;71:1200–1206.
Syrris P, Ward D, Asimaki A, et al. Clinical expression of plakophilin-2 mutations in familial arrhythmogenic right ventricular cardiomyopathy. Circulation 2006;113:356–364.
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Exon number and transcript length for the canine plakophilin-2, plakoglobin, desmoplakin, and desmoglein-2 genes