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United States Department of Agriculture

Agricultural Research Service

Research Project: HOST IMMUNOGENETICS PREDICT CLINICAL DISEASES IN OVINE PROGRESSIVE PNEUMONIA VIRUS INFECTED SHEEP Title: Genome-wide association identifies a deletion in the 3’ untranslated region of Striatin in a canine model of arrhythmogenic right ventricular cardiomyopathy

Authors
item Meurs, Kathryn -
item Mauceli, Evan -
item Lahmers, Sunshine -
item Acland, Gregory -
item White, Stephen
item Lindblad-Toh, Kerstin -

Submitted to: Human Genetics
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: June 18, 2010
Publication Date: July 2, 2010
Citation: Meurs, K.M., Mauceli, E., Lahmers, S., Acland, G.M., White, S.N., Lindblad-Toh, K. 2010. Genome-wide association identifies a deletion in the 3’ untranslated region of Striatin in a canine model of arrhythmogenic right ventricular cardiomyopathy. Human Genetics. 128:315-324.

Interpretive Summary: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited form of heart disease characterized by excessive heart rate and sudden cardiac death. It is most frequently inherited as a dominant trait, though not all individuals with a mutation develop disease and those that do progress to disease develop it at differing ages and with variable clinical presentation. The human disease is most commonly associated with a causative mutation in one of several genes encoding a desmosomal protein, which generally function to hold muscle cells together and/or enable communication between them. We have previously described a canine model of ARVC in the boxer dog. We collected clinical data on adult boxer dogs for ARVC by performing physical examination, echocardiogram and ambulatory electrocardiogram. A canine genotyping array was used that contains 50,000 genetic markers spaced roughly equally across the entire dog genome. Genome-wide association using this array identified several genetic regions of association with ARVC, of which the strongest resided on chromosome 17. Within this region, fine-mapping and direct DNA sequencing identified a deletion of eight base pairs in the 3’ untranslated region (UTR) of the Striatin gene that was associated with ARVC in the boxer dog. Transcripts of the Striatin gene with this deletion are predicted to fold differently than the more common form of the gene, and gene expression experiments confirm lower levels of gene expression when the deletion is present. Immunofluorescence studies showed that Striatin is found in the desmosomal region of cardiac muscle cells, and it is found in close physical proximity to 3 other proteins previously shown to be involved with ARVC. In summary, we describe an 8 base pair deletion in the 3’UTR of a novel desmosomal gene, Striatin, in this canine model of ARVC. Striatin is a desmosomal protein with both calcium dependent calmodulin and caveolin binding sites. We suggest that because Striatin is associated with ARVC in dogs and is found with other known ARVC proteins in the cardiac desmosome, Striatin may serve as an important gene to screen for human ARVC.

Technical Abstract: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a familial cardiac disease characterized by rapid ventricular tachycardia 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 a desmosomal protein. 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 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. Immunofluorescence studies localized Striatin to the desmosomal region of the cardiac myocyte and co-localized it to three other desmosomal proteins, Plakophilin- 2, Plakoglobin and Desmoplakin. In this study we describe an 8 base pair deletion in the 3’UTR of a novel desmosomal gene, Striatin, in this canine model of ARVC. Striatin is a desmosomal protein with both calcium dependent calmodulin and caveolin binding sites. We suggest that Striatin may serve as a novel candidate gene for human ARVC.

Last Modified: 10/21/2014
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