title: Dysferlin deficiency confers increased susceptibility to coxsackievirus-induced cardiomyopathy.
abstract: Coxsackievirus infection can lead to viral myocarditis and its sequela, dilated cardiomyopathy, which represent major causes of cardiovascular mortality worldwide in children. Yet, the host genetic susceptible factors and the underlying mechanisms by which viral infection damages cardiac function remain to be fully resolved. Dysferlin is a transmembrane protein highly expressed in skeletal and cardiac muscles. In humans, mutations in the dysferlin gene can cause limb-girdle muscular dystrophy type 2B and Miyoshi myopathy. Dysferlin deficiency has also been linked to cardiomyopathy. Defective muscle membrane repair has been suggested to be an important mechanism responsible for muscle degeneration in dysferlin-deficient patients and animals. Using both naturally occurring and genetically engineered dysferlin-deficient mice, we demonstrated that loss of dysferlin confers increased susceptibility to coxsackievirus infection and myocardial damage. More interestingly, we found that dysferlin is cleaved following coxsackieviral infection through the proteolytic activity of virally encoded proteinases, suggesting an important mechanism underlying virus-induced cardiac dysfunction. Our results in this study not only identify dysferlin deficiency as a novel host risk factor for viral myocarditis but also reveal a key mechanism by which coxsackievirus infection impairs cardiac function, leading to the development of dilated cardiomyopathy.
authors.affiliation: Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, BC, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Chen
authors.initials: C
authors.lastname: Wang
authors.affiliation: Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, BC, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Jerry
authors.initials: J
authors.lastname: Wong
authors.affiliation: Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, BC, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Gabriel
authors.initials: G
authors.lastname: Fung
authors.affiliation: Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, BC, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Junyan
authors.initials: J
authors.lastname: Shi
authors.affiliation: Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, BC, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Haoyu
authors.initials: H
authors.lastname: Deng
authors.affiliation: Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, BC, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Jingchun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, BC, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Pascal
authors.initials: P
authors.lastname: Bernatchez
authors.affiliation: Centre for Heart Lung Innovation, St. Paul's Hospital, Vancouver, BC, Canada.|Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Honglin
authors.initials: H
authors.lastname: Luo
mesh_terms: D000818:Animals; D003384:Coxsackievirus Infections / Q000235:genetics* / Q000473:pathology*; D000073939:Dysferlin; D020022:Genetic Predisposition to Disease; D008565:Membrane Proteins / Q000172:deficiency*; D051379:Mice; D009205:Myocarditis / Q000235:genetics* / Q000473:pathology*
chemical_list: C497505:Dysf protein, mouse; D000073939:Dysferlin; D008565:Membrane Proteins