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

Perez, Carmelo; Wangueemert, Fernando; Perez, Guillermo J.; 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


Carmelo Perez

Fernando Wangueemert

Guillermo J. Perez

Fernando Wangüemert

Cristina Bosch Calero

Carmelo Pérez

Oscar Campuzano

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Dr Pedro Beltran-Alvarez
Senior Lecturer in Health and Climate Change and Programme co-Director of the MSc Health and Climate Change

Fabiana S. Scornik

Anna Iglesias

Paola Berne

Catarina Allegue

Pablo M. Ruiz Hernandez

Josep Brugada

Guillermo J. Pérez

Ramon Brugada


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.


Wangüemert, F., Bosch Calero, C., Pérez, C., Campuzano, O., Beltran-Alvarez, P., Scornik, F. S., …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.

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 Oct 27, 2022
Journal Heart rhythm
Print ISSN 1547-5271
Electronic ISSN 1556-3871
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 12
Issue 7
Pages 1636-1643
Keywords Physiology (medical); Cardiology and Cardiovascular Medicine
Public URL
Publisher URL
Additional Information Author's accepted manuscript of article published in: Heart rhythm, 2015, v.12, issue 7


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