Clinical and molecular characterization of a cardiac ryanodine receptor founder mutation causing catecholaminergic polymorphic ventricular tachycardia

Wangüemert, Fernando; Bosch Calero, Cristina; Pérez, Carmelo; Campuzano, Oscar; Beltran-Alvarez, Pedro; Scornik, Fabiana S.; Iglesias, Anna; Berne, Paola; Allegue, Catarina; Ruiz Hernandez, Pablo M.; Brugada, Josep; Pérez, Guillermo J.; Brugada, Ramon

Abstract

Background Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a difficult-to-diagnose cause of sudden cardiac death (SCD). We identified a family of 1400 individuals with multiple cases of CPVT, including 36 SCDs during youth. Objectives We sought to identify the genetic cause of CPVT in this family, to preventively treat and clinically characterize the mutation-positive individuals, and to functionally characterize the pathogenic mechanisms of the mutation. Methods Genetic testing was performed for 1404 relatives. Mutation-positive individuals were preventively treated with β-blockers and clinically characterized with a serial exercise treadmill test (ETT) and Holter monitoring. In vitro functional studies included caffeine sensitivity and store overload–induced calcium release activity of the mutant channel in HEK293 cells. Results We identified the p.G357S_RyR2 mutation, in the cardiac ryanodine receptor, in 179 family members and in 6 SCD cases. No SCD was observed among treated mutation-positive individuals over a median follow-up of 37 months; however, 3 relatives who had refused genetic testing (confirmed mutation-positive individuals) experienced SCD. Holter monitoring did not provide relevant information for CPVT diagnosis. One single ETT was unable to detect complex cardiac arrhythmias in 72% of mutation-positive individuals, though the serial ETT improved the accuracy. Functional studies showed that the G357S mutation increased caffeine sensitivity and store overload–induced calcium release activity under conditions that mimic catecholaminergic stress. Conclusion Our study supports the use of genetic testing to identify individuals at risk of SCD to undertake prophylactic interventions. We also show that the pathogenic mechanisms of p.G357S_RyR2 appear to depend on β-adrenergic stimulation.

Citation

Wangüemert, F., Bosch Calero, C., Pérez, C., Campuzano, O., Beltran-Alvarez, P., Scornik, F. S., Iglesias, A., Berne, P., Allegue, C., Ruiz Hernandez, P. M., Brugada, J., Pérez, G. J., & Brugada, R. (2015). Clinical and molecular characterization of a cardiac ryanodine receptor founder mutation causing catecholaminergic polymorphic ventricular tachycardia. Heart rhythm : the official journal of the Heart Rhythm Society, 12(7), 1636-1643. https://doi.org/10.1016/j.hrthm.2015.03.033

• Journal Article Type: Article
• Acceptance Date: Mar 1, 2015
• Online Publication Date: Mar 23, 2015
• Publication Date: Jul 1, 2015
• Deposit Date: Mar 11, 2016
• Publicly Available Date: Mar 11, 2016
• Journal: Heart rhythm
• Print ISSN: 1547-5271
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 12
• Issue: 7
• Pages: 1636-1643
• DOI: https://doi.org/10.1016/j.hrthm.2015.03.033
• Keywords: Physiology (medical); Cardiology and Cardiovascular Medicine
• Public URL: https://hull-repository.worktribe.com/output/412811
• Publisher URL: http://www.sciencedirect.com/science/article/pii/S154752711500332X
• Additional Information: Author's accepted manuscript of article published in: Heart rhythm, 2015, v.12, issue 7
• Contract Date: Mar 11, 2016