title: Generation and characterization of a mouse model harboring the exon-3 deletion in the cardiac ryanodine receptor.
abstract: A large genomic deletion in human cardiac ryanodine receptor (RYR2) gene has been detected in a number of unrelated families with various clinical phenotypes, including catecholaminergic polymorphic ventricular tachycardia (CPVT). This genomic deletion results in an in-frame deletion of exon-3 (Ex3-del). To understand the underlying disease mechanism of the RyR2 Ex3-del mutation, we generated a mouse model in which the RyR2 exon-3 sequence plus 15-bp intron sequences flanking exon-3 were deleted. Heterozygous Ex3-del mice (Ex3-del+/-) survived, but no homozygous Ex3-del mice were born. Unexpectedly, the Ex3-del+/- mice are not susceptible to CPVT. Ex3-del+/- cardiomyocytes exhibited similar amplitude but altered dynamics of depolarization-induced Ca2+ transients compared to wild type (WT) cells. Immunoblotting analysis revealed markedly reduced expression of RyR2 protein in the Ex3-del+/- mutant heart, indicating that Ex3-del has a major impact on RyR2 protein expression in mice. Cardiac specific, conditional knockout of the WT RyR2 allele in Ex3-del+/- mice led to bradycardia and death. Thus, the absence of CPVT and other phenotypes in Ex3-del+/- mice may be attributable to the predominant expression of the WT RyR2 allele as a result of the markedly reduced expression of the Ex3-del mutant allele. The effect of Ex3-del on RyR2 protein expression is discussed in relation to the phenotypic variability in individuals with the RyR2 exon-3 deletion.
authors.affiliation: Libin Cardiovascular Institute of Alberta, Departments of Physiology & Pharmacology, and Biochemistry & Molecular Biology, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Yingjie
authors.initials: Y
authors.lastname: Liu
authors.affiliation: Libin Cardiovascular Institute of Alberta, Departments of Physiology & Pharmacology, and Biochemistry & Molecular Biology, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Ruiwu
authors.initials: R
authors.lastname: Wang
authors.affiliation: Libin Cardiovascular Institute of Alberta, Departments of Physiology & Pharmacology, and Biochemistry & Molecular Biology, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Bo
authors.initials: B
authors.lastname: Sun
authors.affiliation: Libin Cardiovascular Institute of Alberta, Departments of Physiology & Pharmacology, and Biochemistry & Molecular Biology, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Tao
authors.initials: T
authors.lastname: Mi
authors.affiliation: Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, Illinois, United States of America.
authors.forename: Jingqun
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Yongxin
authors.initials: Y
authors.lastname: Mu
authors.affiliation: Department of Medicine, University of California San Diego, La Jolla, California, United States of America.
authors.forename: Ju
authors.initials: J
authors.lastname: Chen
authors.affiliation: Cardiovascular Research Group, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bround
authors.affiliation: Cardiovascular Research Group, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: James D
authors.initials: JD
authors.lastname: Johnson
authors.affiliation: Libin Cardiovascular Institute of Alberta, Departments of Physiology & Pharmacology, and Biochemistry & Molecular Biology, University of Calgary, Calgary, Alberta, Canada.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Gillis
authors.affiliation: Libin Cardiovascular Institute of Alberta, Departments of Physiology & Pharmacology, and Biochemistry & Molecular Biology, University of Calgary, Calgary, Alberta, Canada; Department of Molecular Biophysics and Physiology, Rush University Medical Center, Chicago, Illinois, United States of America.
authors.forename: S R Wayne
authors.initials: SR
authors.lastname: Chen
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D005091:Exons / Q000235:genetics*; D051379:Mice; D019837:Ryanodine Receptor Calcium Release Channel / Q000235:genetics*; D017180:Tachycardia, Ventricular / Q000235:genetics; D000098850:Polymorphic Catecholaminergic Ventricular Tachycardia
chemical_list: D019837:Ryanodine Receptor Calcium Release Channel
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