Novel CPVT-Associated Calmodulin Mutation in CALM3 (CALM3-A103V) Activates Arrhythmogenic Ca Waves and Sparks
| Autor: | Nieves Gomez-Hurtado, Florentin R. Nitu, Michael J. Ackerman, Jennifer Sun, Bjorn C. Knollmann, Melissa L. Calvert, Dmytro O. Kryshtal, Nicole J. Boczek, Walter J. Chazin, David J. Tester, Christopher N. Johnson, Razvan L. Cornea |
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| Rok vydání: | 2016 |
| Předmět: |
Adult
Male 0301 basic medicine medicine.medical_specialty Genotype Calmodulin Long QT syndrome DNA Mutational Analysis Action Potentials 030204 cardiovascular system & hematology Catecholaminergic polymorphic ventricular tachycardia Ryanodine receptor 2 QT interval Article Electrocardiography Mice 03 medical and health sciences 0302 clinical medicine Physiology (medical) Internal medicine medicine Animals Humans Dominance (genetics) biology Ryanodine business.industry Ryanodine receptor Calcium channel medicine.disease Long QT Syndrome Phenotype 030104 developmental biology Endocrinology Exercise Test Tachycardia Ventricular biology.protein Female Cardiology and Cardiovascular Medicine business |
| Zdroj: | Circulation: Arrhythmia and Electrophysiology. 9 |
| ISSN: | 1941-3084 1941-3149 |
| DOI: | 10.1161/circep.116.004161 |
| Popis: | Background— Calmodulin (CaM) mutations are associated with severe forms of long QT syndrome and catecholaminergic polymorphic ventricular tachycardia (CPVT). CaM mutations are found in 13% of genotype-negative long QT syndrome patients, but the prevalence of CaM mutations in genotype-negative CPVT patients is unknown. Here, we identify and characterize CaM mutations in 12 patients with genotype-negative but clinically diagnosed CPVT. Methods and Results— We performed mutational analysis of CALM1 , CALM2 , and CALM3 gene-coding regions, in vitro measurement of CaM-Ca 2+ (Ca)-binding affinity, ryanodine receptor 2–CaM binding, Ca handling, L-type Ca current, and action potential duration. We identified a novel CaM mutation—A103V—in CALM3 in 1 of 12 patients (8%), a female who experienced episodes of exertion-induced syncope since age 10, had normal QT interval, and displayed ventricular ectopy during stress testing consistent with CPVT. A103V modestly lowered CaM Ca-binding affinity (3-fold reduction versus WT-CaM), but did not alter CaM binding to ryanodine receptor 2. In permeabilized cardiomyocytes, A103V-CaM (100 nmol/L) promoted spontaneous Ca wave and spark activity, a cellular phenotype of ryanodine receptor 2 activation. Even a 1:3 mixture of A103V-CaM:WT-CaM activated Ca waves, demonstrating functional dominance. Compared with long QT syndrome D96V-CaM, A103V-CaM had significantly less effects on L-type Ca current inactivation, did not alter action potential duration, and caused delayed afterdepolarizations and triggered beats in intact cardiomyocytes. Conclusions— We discovered a novel CPVT mutation in the CALM3 gene that shares functional characteristics with established CPVT-associated mutations in CALM1 . A small proportion of A103V-CaM is sufficient to evoke arrhythmogenic Ca disturbances via ryanodine receptor 2 dysregulation, which explains the autosomal dominant inheritance. |
| Databáze: | OpenAIRE |
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