Genome-wide association identifies a deletion in the 3′ untranslated region of Striatin in a canine model of arrhythmogenic right ventricular cardiomyopathy

Abstract

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial cardiac disease characterized by ventricular arrhythmias and sudden cardiac death. It is most frequently inherited as an autosomal dominant trait with incomplete and age-related penetrance and variable clinical expression. The human disease is most commonly associated with a causative mutation in one of several genes encoding desmosomal proteins.We have previously described a spontaneous canine model of ARVC in the boxer dog. We phenotyped adult boxer dogs for ARVC by performing physical examination, echocardiogram and ambulatory electrocardiogram. Genome-wide association using the canine 50k SNP array identified several regions of association, of which the strongest resided on chromosome 17. Fine-mapping and direct DNA sequencing identified an eight base pair deletion in the 3' untranslated region (UTR) of the striatin (STRN) gene on chromosome 17 in association with ARVC in the boxer dog. Evaluation of the secondary structure of the 3' UTR demonstrated that the deletion affects a stem loop structure of the mRNA and expression analysis identified a reduction in striatin mRNA. Dogs that were homozygous for the deletion had a more severe form of disease based on a significantly higher number of ventricular premature complexes. Immunofluorescence studies localized striatin to the intercalated disc region of the cardiac myocyte and co-localized it to three desmosomal proteins, plakophilin-2, plakoglobin and desmoplakin, all involved in the pathogenesis of ARVC in human beings.We suggest that striatin may serve as a novel candidate gene for human ARVC.

Histological Characterization of Dilated Cardiomyopathy in the Juvenile Toy Manchester Terrier

“…The lesion distribution could also provide insights into the possible mechanism/cause of the disease. 31,33 In most cases of canine DCM, the underlying cause is not determined, 44 and other myocardial diseases can produce identical clinical manifestations. It is clear that gross dilative change seen at necropsy may be the result of a variety of myocardial insults or underlying mechanisms.…”

24-hour Holter Monitoring and Troponin I Level in Boxers with Arrhythmogenic Right Ventricular Cardiomyopathy

“…ARVC is described as a disease that has an autosomal dominant trait with reduced penetrance that appears in dogs two to eight years old 5 . This breed is used as a model for research on ARVC 6 . Single cases of ARVC were noticed in breeds such as Syberian Husky, Labrador Retriever and English Bulldog [7][8][9] .…”

SCN5A mutation in Chinese patients with arrhythmogenic right ventricular dysplasia

“…As is common with most hereditary diseases, ARVD also exhibits genetic heterogeneity. Mutations in nondesmosomal proteins such as transmembrane protein 43 (TMEM43) [9], ryanodine receptor 2 (RYR2) [10], desmin, lamins A and C [11], striatin [12], titin [13], and transforming growth factor-β3 (TGF-β3) [14] have been reported to be associated with ARVD. These nondesmosomal proteins, however, have direct or indirect impacts on desmosomal proteins.…”