Clinical Phenotype and Functional Characterization of CASQ2 Mutations Associated With Catecholaminergic Polymorphic Ventricular Tachycardia
- 5 September 2006
- journal article
- research article
- Published by Ovid Technologies (Wolters Kluwer Health) in Circulation
- Vol. 114 (10), 1012-1019
- https://doi.org/10.1161/circulationaha.106.623793
Abstract
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.Keywords
This publication has 24 references indexed in Scilit:
- Calsequestrin mutant D307H exhibits depressed binding to its protein targets and a depressed response to calciumCardiovascular Research, 2004
- Comparing Skeletal and Cardiac Calsequestrin Structures and Their Calcium BindingPublished by Elsevier BV ,2004
- Polymerization of CalsequestrinPublished by Elsevier BV ,2003
- Targeting of alpha-kinase-anchoring protein (alphaKAP) to sarcoplasmic reticulum and nuclei of skeletal muscleBiochemical Journal, 2003
- Crystal structure of calsequestrin from rabbit skeletal muscle sarcoplasmic reticulumNature Structural & Molecular Biology, 1998
- Regulation of Ca2+ signaling in transgenic mouse cardiac myocytes overexpressing calsequestrin.JCI Insight, 1998
- Coexpression of two isoforms of calsequestrin in rabbit slow-twitch muscleJournal of Muscle Research and Cell Motility, 1990
- A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye bindingAnalytical Biochemistry, 1976
- Fractionation of solubilized sarcoplasmic reticulum?Biochemical and Biophysical Research Communications, 1971
- Cleavage of Structural Proteins during the Assembly of the Head of Bacteriophage T4Nature, 1970