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(Circulation Research. 2008;103:298.)
© 2008 American Heart Association, Inc.

Integrative Physiology

Unexpected Structural and Functional Consequences of the R33Q Homozygous Mutation in Cardiac Calsequestrin

A Complex Arrhythmogenic Cascade in a Knock In Mouse Model

Nicoletta Rizzi^*, Nian Liu^*, Carlo Napolitano, Alessandra Nori, Federica Turcato, Barbara Colombi, Silvio Bicciato, Diego Arcelli, Alessandro Spedito, Mario Scelsi, Laura Villani, Giovanni Esposito, Simona Boncompagni, Feliciano Protasi, Pompeo Volpe, Silvia G. Priori

From Molecular Cardiology (N.R., N.L., C.N., B.C., S.G.P.), IRCCS Fondazione S. Maugeri, Pavia, Italy; the Department of Cardiology (S.G.P.), University of Pavia, Italy; the Department of Experimental Biomedical Sciences (A.N., F.T., P.V.), University of Padova, Italy; the Department of Biomedical Sciences (S. Bicciato), University of Modena and Reggio Emilia, Modena, Italy; the Istituto Dermopatico dell' Immacolata (IDI) – IRCCS (D.A.), Molecular Oncology Laboratory, Bioinformatics Unit - Roma, Italy; the Department of Animal Biology (A.S.), University of Pavia, Italy; the Pathology Division IRCCS Fondazione S. Maugeri (M.S., L.V.), Pavia, Italy; the Department of Cardiology (G.E.), University Federico II of Napoli, Italy; and IIM - Interuniversitary Institute of Miology & CeSI (S. Boncompagni, F.P.), University G. d'Annunzio, Chieti, Italy.

Correspondence to Silvia G. Priori, MD, PhD, Molecular Cardiology, Maugeri Foundation, University of Pavia, Via Ferrata 8, 27100-Pavia-Italy. E-mail spriori{at}fsm.it

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited arrhythmogenic disorder characterized by life threatening arrhythmias elicited by physical and emotional stress in young individuals. The recessive form of CPVT is associated with mutation in the cardiac calsequestrin gene (CASQ2). We engineered and characterized a homozygous CASQ2^R33Q/R33Q mouse model that closely mimics the clinical phenotype of CPVT patients. CASQ2^R33Q/R33Q mice develop bidirectional VT on exposure to environmental stress whereas CASQ2^R33Q/R33Q myocytes show reduction of the sarcoplasmic reticulum (SR) calcium content, adrenergically mediated delayed (DADs) and early (EADs) afterdepolarizations leading to triggered activity. Furthermore triadin, junctin, and CASQ2-R33Q proteins are significantly decreased in knock-in mice despite normal levels of mRNA, whereas the ryanodine receptor (RyR2), calreticulin, phospholamban, and SERCA2a-ATPase are not changed. Trypsin digestion studies show increased susceptibility to proteolysis of mutant CASQ2. Despite normal histology, CASQ2^R33Q/R33Q hearts display ultrastructural changes such as disarray of junctional electron-dense material, referable to CASQ2 polymers, dilatation of junctional SR, yet normal total SR volume. Based on the foregoings, we propose that the phenotype of the CASQ2^R33Q/R33Q CPVT mouse model is portrayed by an unexpected set of abnormalities including (1) reduced CASQ2 content, possibly attributable to increased degradation of CASQ2-R33Q, (2) reduction of SR calcium content, (3) dilatation of junctional SR, and (4) impaired clustering of mutant CASQ2.

Key Words: sudden death • genetics • calsequestrin • triggered activity • transgenic mice

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Luigi A. Venetucci and David A. Eisner
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