title: Clinical phenotype and functional characterization of CASQ2 mutations associated with catecholaminergic polymorphic ventricular tachycardia.
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.
  
  
  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 Ca2+, whereas CASQ2(L167H) had normal calcium-binding properties. When expressed in rat myocytes, both mutants decreased the sarcoplasmic reticulum Ca2+-storing capacity and reduced the amplitude of I(Ca)-induced Ca2+ transients and of spontaneous Ca2+ 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 Ca2+ 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.
authors.affiliation: Molecular Cardiology, IRCCS Fondazione Maugeri, University of Pavia, Via Ferrata 8 27100, Pavia, Italy.
authors.forename: Marina Raffaele
authors.initials: MR
authors.lastname: di Barletta
authors.forename: Serge
authors.initials: S
authors.lastname: Viatchenko-Karpinski
authors.forename: Alessandra
authors.initials: A
authors.lastname: Nori
authors.forename: Mirella
authors.initials: M
authors.lastname: Memmi
authors.forename: Dmitry
authors.initials: D
authors.lastname: Terentyev
authors.forename: Federica
authors.initials: F
authors.lastname: Turcato
authors.forename: Giorgia
authors.initials: G
authors.lastname: Valle
authors.forename: Nicoletta
authors.initials: N
authors.lastname: Rizzi
authors.forename: Carlo
authors.initials: C
authors.lastname: Napolitano
authors.forename: Sandor
authors.initials: S
authors.lastname: Gyorke
authors.forename: Pompeo
authors.initials: P
authors.lastname: Volpe
authors.forename: Silvia G
authors.initials: SG
authors.lastname: Priori
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D002155:Calsequestrin / Q000235:genetics*; D002648:Child; D005260:Female; D018014:Gene Transfer Techniques; D006580:Genetic Carrier Screening; D006801:Humans; D008297:Male; D032342:Muscle Cells / Q000502:physiology; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D010375:Pedigree; D017354:Point Mutation; D051381:Rats; D013575:Syncope / Q000235:genetics*; D017180:Tachycardia, Ventricular / Q000235:genetics* / Q000503:physiopathology; D014162:Transfection
chemical_list: C443109:CASQ2 protein, human; D002155:Calsequestrin