1338 AJVR, Vol 68, No. 12, December 2007 A rrhythmogenic right ventricular cardiomyopa- thy is a familial cardiomyopathy characterized by progressive right (and sometimes left) ventricular and interventricular myocardial atrophy and fibrofatty re- placement. 1-4 Clinically, ARVC is characterized by ven- tricular 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 Desmosomal gene evaluation in Boxers with arrhythmogenic right ventricular cardiomyopathy Kathryn M. Meurs, DVM, PhD; Martina M. Ederer, PhD; Joshua A. Stern, BS Objective—To sequence the exonic and splice site regions of the 4 desmosomal genes as- sociated with the human form of familial arrhythmogenic right ventricular cardiomyopathy (ARVC) in Boxers with ARVC and identify a causative mutation. Animals—10 unrelated Boxers with ARVC and 2 unaffected Labrador Retrievers (control dogs). Procedures—Exonic and splice site regions of the 4 genes encoding the desmosomal proteins plakophilin-2, plakoglobin, desmoplakin, and desmoglein-2 were sequenced. Se- quences were compared for nucleotide sequence changes between affected dogs and the published sequences for clinically normal dogs and between affected dogs and the control dogs. Base-pair changes were considered to be causative for ARVC if they were detected in an affected dog but not in unaffected dogs, and if they involved a conserved amino acid and changed that amino acid to one of a different polarity, acid-base status, or structure. Results—A causative mutation for ARVC in Boxers was not identified, although single nucleotide polymorphisms were detected in some affected dogs within exon 3 of the pla- kophilin-2 gene; exon 3 of the plakoglobin gene; exons 3 and 7 of the desmoglein-2 gene; and exons 6, 14, 15, and 24 of the desmoplakin gene. None of these changed the amino acid of the respective protein. Conclusions and Clinical Relevance—Mutations within the desmosomal genes associ- ated with the development of ARVC in humans do not appear to be causative for ARVC in Boxers. Genome-wide scanning for genetic loci of interest in dogs should be pursued. (Am J Vet Res 2007;68:1338–1341) The genetic evaluation of ARVC in humans has identified 9 different loci and 6 different causative genes. 6-8 An autosomal dominant pattern of inheritance with variable penetrance is most common. 5,6 Because 4 of the reported genes that contain caus- ative mutations encode desmosomal proteins, it has been proposed that ARVC is a disease of the desmo- some. 8 Desmosomes are multiprotein complexes locat- ed 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 cytoskele- ton. 3,9 Causative mutations have been identified in the 3 genes that encode desmoplakin, plakoglobin, and plakophilin-2; these desmosomal proteins are respon- sible for the mechanical coupling of the myocytes and provide a continuous cell-to-cell connection to the sar- comeric 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 caus- ative mutations for ARVC within genes encoding des- mosomal proteins has led to the proposal that ARVC is Received February 19, 2007. Accepted April 24, 2007. From the Department of Veterinary Clinical Sciences, College of Veterinary Medicine, Washington State University, Pullman, WA 99164 (Meurs, Ederer); and the Department of Veterinary Clinical Sciences, College of Veterinary Medicine, The Ohio State University, Columbus, OH 43210 (Stern). Address correspondence to Dr. Meurs. ABBREVIATIONS ARVC Arrhythmogenic right ventricular cardiomyopathy TGF-β3 Transforming growth factor–β3 dNTP Deoxynucleoside triphosphate