Clinical Phenotype and Functional Characterization of <i>CASQ2</i> Mutations Associated With Catecholaminergic Polymorphic Ventricular Tachycardia

• Marina Raffaele di Barletta

  From Molecular Cardiology (M.R.d.B., M.M., N.R., C.N., S.G.P.), IRCCS Fondazione Maugeri, Pavia, Italy; Department of Cardiology (S.G.P.), University of Pavia, Pavia, Italy; Dorothy Davis Heart and Lung Research Institute (S.V.-K., D.T., S.G.), Ohio State University, Columbus; and Department of Experimental Biomedical Sciences (A.N., F.T., G.V., P.V.), University of Padova, Padova, Italy.

• Serge Viatchenko-Karpinski

  From Molecular Cardiology (M.R.d.B., M.M., N.R., C.N., S.G.P.), IRCCS Fondazione Maugeri, Pavia, Italy; Department of Cardiology (S.G.P.), University of Pavia, Pavia, Italy; Dorothy Davis Heart and Lung Research Institute (S.V.-K., D.T., S.G.), Ohio State University, Columbus; and Department of Experimental Biomedical Sciences (A.N., F.T., G.V., P.V.), University of Padova, Padova, Italy.

• Alessandra Nori

  From Molecular Cardiology (M.R.d.B., M.M., N.R., C.N., S.G.P.), IRCCS Fondazione Maugeri, Pavia, Italy; Department of Cardiology (S.G.P.), University of Pavia, Pavia, Italy; Dorothy Davis Heart and Lung Research Institute (S.V.-K., D.T., S.G.), Ohio State University, Columbus; and Department of Experimental Biomedical Sciences (A.N., F.T., G.V., P.V.), University of Padova, Padova, Italy.

• Mirella Memmi

  From Molecular Cardiology (M.R.d.B., M.M., N.R., C.N., S.G.P.), IRCCS Fondazione Maugeri, Pavia, Italy; Department of Cardiology (S.G.P.), University of Pavia, Pavia, Italy; Dorothy Davis Heart and Lung Research Institute (S.V.-K., D.T., S.G.), Ohio State University, Columbus; and Department of Experimental Biomedical Sciences (A.N., F.T., G.V., P.V.), University of Padova, Padova, Italy.

• Dmitry Terentyev

  From Molecular Cardiology (M.R.d.B., M.M., N.R., C.N., S.G.P.), IRCCS Fondazione Maugeri, Pavia, Italy; Department of Cardiology (S.G.P.), University of Pavia, Pavia, Italy; Dorothy Davis Heart and Lung Research Institute (S.V.-K., D.T., S.G.), Ohio State University, Columbus; and Department of Experimental Biomedical Sciences (A.N., F.T., G.V., P.V.), University of Padova, Padova, Italy.

• Federica Turcato

  From Molecular Cardiology (M.R.d.B., M.M., N.R., C.N., S.G.P.), IRCCS Fondazione Maugeri, Pavia, Italy; Department of Cardiology (S.G.P.), University of Pavia, Pavia, Italy; Dorothy Davis Heart and Lung Research Institute (S.V.-K., D.T., S.G.), Ohio State University, Columbus; and Department of Experimental Biomedical Sciences (A.N., F.T., G.V., P.V.), University of Padova, Padova, Italy.

• Giorgia Valle

  From Molecular Cardiology (M.R.d.B., M.M., N.R., C.N., S.G.P.), IRCCS Fondazione Maugeri, Pavia, Italy; Department of Cardiology (S.G.P.), University of Pavia, Pavia, Italy; Dorothy Davis Heart and Lung Research Institute (S.V.-K., D.T., S.G.), Ohio State University, Columbus; and Department of Experimental Biomedical Sciences (A.N., F.T., G.V., P.V.), University of Padova, Padova, Italy.

• Nicoletta Rizzi

  From Molecular Cardiology (M.R.d.B., M.M., N.R., C.N., S.G.P.), IRCCS Fondazione Maugeri, Pavia, Italy; Department of Cardiology (S.G.P.), University of Pavia, Pavia, Italy; Dorothy Davis Heart and Lung Research Institute (S.V.-K., D.T., S.G.), Ohio State University, Columbus; and Department of Experimental Biomedical Sciences (A.N., F.T., G.V., P.V.), University of Padova, Padova, Italy.

• Carlo Napolitano

  From Molecular Cardiology (M.R.d.B., M.M., N.R., C.N., S.G.P.), IRCCS Fondazione Maugeri, Pavia, Italy; Department of Cardiology (S.G.P.), University of Pavia, Pavia, Italy; Dorothy Davis Heart and Lung Research Institute (S.V.-K., D.T., S.G.), Ohio State University, Columbus; and Department of Experimental Biomedical Sciences (A.N., F.T., G.V., P.V.), University of Padova, Padova, Italy.

• Sandor Gyorke

  From Molecular Cardiology (M.R.d.B., M.M., N.R., C.N., S.G.P.), IRCCS Fondazione Maugeri, Pavia, Italy; Department of Cardiology (S.G.P.), University of Pavia, Pavia, Italy; Dorothy Davis Heart and Lung Research Institute (S.V.-K., D.T., S.G.), Ohio State University, Columbus; and Department of Experimental Biomedical Sciences (A.N., F.T., G.V., P.V.), University of Padova, Padova, Italy.

• Pompeo Volpe

  From Molecular Cardiology (M.R.d.B., M.M., N.R., C.N., S.G.P.), IRCCS Fondazione Maugeri, Pavia, Italy; Department of Cardiology (S.G.P.), University of Pavia, Pavia, Italy; Dorothy Davis Heart and Lung Research Institute (S.V.-K., D.T., S.G.), Ohio State University, Columbus; and Department of Experimental Biomedical Sciences (A.N., F.T., G.V., P.V.), University of Padova, Padova, Italy.

• Silvia G. Priori

  From Molecular Cardiology (M.R.d.B., M.M., N.R., C.N., S.G.P.), IRCCS Fondazione Maugeri, Pavia, Italy; Department of Cardiology (S.G.P.), University of Pavia, Pavia, Italy; Dorothy Davis Heart and Lung Research Institute (S.V.-K., D.T., S.G.), Ohio State University, Columbus; and Department of Experimental Biomedical Sciences (A.N., F.T., G.V., P.V.), University of Padova, Padova, Italy.

抄録

Background— Four distinct mutations in the human cardiac calsequestrin gene ( CASQ2 ) have been linked to catecholaminergic polymorphic ventricular tachycardia (CPVT). The mechanisms leading to the clinical phenotype are still poorly understood because only 1 CASQ2 mutation has been characterized in vitro. Methods and Results— We identified a homozygous 16-bp deletion at position 339 to 354 leading to a frame shift and a stop codon after 5aa (CASQ2 G112+5X ) in a child with stress-induced ventricular tachycardia and cardiac arrest. The same deletion was also identified in association with a novel point mutation (CASQ2 L167H ) in a highly symptomatic CPVT child who is the first CPVT patient carrier of compound heterozygous CASQ2 mutations. We characterized in vitro the properties of CASQ2 mutants: CASQ2 G112+5X did not bind Ca 2+ , whereas CASQ2 L167H had normal calcium-binding properties. When expressed in rat myocytes, both mutants decreased the sarcoplasmic reticulum Ca 2+ -storing capacity and reduced the amplitude of I Ca -induced Ca 2+ transients and of spontaneous Ca 2+ sparks in permeabilized myocytes. Exposure of myocytes to isoproterenol caused the development of delayed afterdepolarizations in CASQ2 G112+5X . Conclusions— CASQ2 L167H and CASQ2 G112+5X alter CASQ2 function in cardiac myocytes, which leads to reduction of active sarcoplasmic reticulum Ca 2+ release and calcium content. In addition, CASQ2 G112+5X displays altered calcium-binding properties and leads to delayed afterdepolarizations. We conclude that the 2 CASQ2 mutations identified in CPVT create distinct abnormalities that lead to abnormal intracellular calcium regulation, thus facilitating the development of tachyarrhythmias.

収録刊行物

• Circulation

  Circulation 114 (10), 1012-1019, 2006-09-05

  Ovid Technologies (Wolters Kluwer Health)

キーワード

• Physiology (medical)
• Cardiology and Cardiovascular Medicine

詳細情報

• CRID: 1360574096392707456
• NII論文ID: 30022672779
• DOI: 10.1161/circulationaha.106.623793
• ISSN: 15244539
• ISSN: 00097322
• Web Site: https://www.ahajournals.org/doi/full/10.1161/CIRCULATIONAHA.106.623793
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