Cited by 933Cardiac electrophysiology and arrhythmiasIon channel regulation and functionCardiovascular Effects of Exercise

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Loss-of-Function Mutations in the Cardiac Calcium Channel Underlie a New Clinical Entity Characterized by ST-Segment Elevation, Short QT Intervals, and Sudden Cardiac Death

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Antzelevitch, Charles, Pollevick, Guido D., Cordeiro, Jonathan M., Casis, Oscar, Sanguinetti, Michael C., Aizawa, Yoshiyasu, Guerchicoff, Alejandra, Pfeiffer, Ryan, Oliva, Antonio, Wollnik, Bernd, Gelber, Philip, Bonaros, Elias P., Burashnikov, Elena, Wu, Yuesheng, Sargent, John D., Schickel, Stefan, Oberheiden, Ralf, Bhatia, Atul, Hsu, Li-Fern, Haïssaguerre, Michel, Schimpf, Rainer, Borggrefe, Martin, Wolpert, Christian·2007·Circulation

DOI 10.1161/circulationaha.106.668392PMC PMC1952683

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Abstract

Background— Cardiac ion channelopathies are responsible for an ever-increasing number and diversity of familial cardiac arrhythmia syndromes. We describe a new clinical entity that consists of an ST-segment elevation in the right precordial ECG leads, a shorter-than-normal QT interval, and a history of sudden cardiac death. Methods and Results— Eighty-two consecutive probands with Brugada syndrome were screened for ion channel gene mutations with direct sequencing. Site-directed mutagenesis was performed, and CHO-K1 cells were cotransfected with cDNAs encoding wild-type or mutant CACNB2b (Ca vβ2b ), CACNA2D1 (Ca vα2δ1 ), and CACNA1C tagged with enhanced yellow fluorescent protein (Ca v 1.2). Whole-cell patch-clamp studies were performed after 48 to 72 hours. Three probands displaying ST-segment elevation and corrected QT intervals ≤360 ms had mutations in genes encoding the cardiac L-type calcium channel. Corrected QT ranged from 330 to 370 ms among probands and clinically affected family members. Rate adaptation of QT interval was reduced. Quinidine normalized the QT interval and prevented stimulation-induced ventricular tachycardia. Genetic and heterologous expression studies revealed loss-of-function missense mutations in CACNA1C (A39V and G490R) and CACNB2 (S481L) encoding the α 1 - and β 2b -subunits of the L-type calcium channel. Confocal microscopy revealed a defect in trafficking of A39V Ca v 1.2 channels but normal trafficking of channels containing G490R Ca v 1.2 or S481L Ca vβ2b -subunits. Conclusions— This is the first report of loss-of-function mutations in genes encoding the cardiac L-type calcium channel to be associated with a familial sudden cardiac death syndrome in which a Brugada syndrome phenotype is combined with shorter-than-normal QT intervals.

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“Mutations in six different genes are described causing the clinical and electrocardiographic phenotype of Brugada syndrome [34, 53–56].”
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Study of the Extent of the Information of Cardiologists from São Paulo City, Brazil, Regarding a Low-Prevalence Entity: Brugada Syndrome
Riera, A. P., Filho, C. F., Uchida, A., Zhang, L., Antzelevitch, C., Schapachnik, E., Dubner, S., & Ferreira, C. (2008) · Annals of Noninvasive Electrocardiology · doi:10.1111/j.1542-474x.2008.00248.x · Cited by 6
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The Molecular Pathophysiology of Atrial Fibrillation
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Disorders of Cardiac Repolarization
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Timothy Syndrome and CACNA1C-Related Disorder: First International Language and Management Guidelines Consensus Statement
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“For BrS and SQTS studies provide only limited support for a link between CACNA1C and those phenotypes, and the causal relationship is disputed (11), as further evidenced by ClinGen’s re-evaluation of the literature (12).”
Influential
ARumenamides: A novel class of potential antiarrhythmic compounds
Abdelsayed, M., Page, D. A., & Ruben, P. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.976903 · Cited by 5
A descriptive report on short QT interval in Kherameh branch of the PERSIAN cohort study
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Brugada syndrome: current diagnostics, epidemiology, genetic data and novel mechanisms (RCD code: V‑1A.1)
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“[124] CACNA1c/B2 ICaL 12p13.”
Supraphysiological Testosterone Levels Shorten the QT Interval but do Not Alter Total Anatomic Myocardial Infarct Size in Rabbits with Acute Myocardial Infarction
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“From two families, mutations in the SCN1B gene were identified leading to a decrease of sodium current and inducing conduction disturbances and an aspect of BrS in some patients.40 More recently, a mutation in MOG1 gene, partner of Nav 1.5, was identified.41 Several gain of function mutations have been described in ge…”
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Coexisting vasospastic angina and undiagnosed Brugada syndrome resulting in cardiac arrest.
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“In addition, the “ mixed ” electro-cardiographic patterns including phenotypic overlap with long QT syndrome, short QT syndrome, or cardiac conduction disease have been reported (Bezzina et al., 1999; Shirai et al., 2002; Antzelevitch et al., 2007).”
Genetic testing for channelopathies, more than ten years progress and remaining challenges
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“2 α-subunit, gives rise to calcium channel “loss-of-function”;[9] CACNB2, encoding the Cav1.”
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Síndrome de Brugada
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Genetics of Arrhythmia: Disease Pathways Beyond Ion Channels
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Brugada Syndrome.
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“mutations in CACNB2b showed channel trafficking impairment.(16) CACNAD1 is another gene encoding a2d subunit of this channel.”
Background
Identifying risk of cardiac events in short QT syndrome.
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Local calcium dynamics and signalling in cardiomyocytes
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“Genetic variants in CACNB2 are linked to sudden cardiac death and arrhythmic syndromes 46,47 .”
In silico modelling of multi‐electrode arrays for enhancing cardiac drug testing on hiPSC‐CM heterogeneous tissues
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“Loss-of-function mutations in these genes impair LTCC expression, trafficking or function, leading to reduced Ca 2 + current (Antzelevitch et al., 2007).”
A narrative review of inherited arrhythmogenic syndromes in young population: role of genetic diagnosis in exercise recommendations
Sarquella-Brugada, G., Martínez-Barrios, E., César, S., Toro, R., Cruzalegui, J., Greco, A., Díez-Escuté, N., Cerralbo, P., Chipa, F., Arbelo, E., et al. (2024) · BMJ Open Sport & Exercise Medicine · doi:10.1136/bmjsem-2023-001852 · Cited by 4
“These especial situations not classified as a definite SQTS. Syncope and SCD often occur during periods of rest or sleep but arrhythmias in exercise situations have been also reported.”
BackgroundInfluential
Bipolar Patient–Specific In Vitro Diagnostic Test Reveals Underlying Cardiac Arrhythmia Phenotype Caused by Calcium Channel Genetic Risk Factor
Dow, R., DeLong, C. J., Jiang, G., Attili, D., Creech, J., Kraan, R., Campbell, K., Saraithong, P., O'Shea, S. K., da Rocha, A. L. M., et al. (2024) · Biological Psychiatry Global Open Science · doi:10.1016/j.bpsgos.2024.100296 · Cited by 4
Functional identification of hot-spot mutations in cardiac calcium channel genes associated with the J wave syndromes
Zeng, B., Zhang, X., Schimpf, R., Powers, A., Glikson, M., Antzelevitch, C., Hu, D., & Barajas-Martinez, H. (2023) · Philosophical Transactions of the Royal Society of London. Biological Sciences · doi:10.1098/rstb.2022.0286 · Cited by 4
Self-citation
Sudden cardiac arrest in a patient with malignant mitral valve prolapse with CACNB2 gene mutation: a simple coincidence or coexistence?—a case report
Parthiban, N., & Sani, H. (2023) · European Heart Journal: Case Reports · doi:10.1093/ehjcr/ytad196 · Cited by 4
“Although the genetic mutation is not part of the diagnostic criteria for Brugada syndrome, numerous studies have demonstrated the association between the loss of function mutation of the cardiac L-type calcium channel and the Brugada syndrome phenotype.(12,13,14) In recent years, the arrhythmogenic potential of MVP ca…”
Background
Brugada syndrome: current concepts and genetic background
Pérez-Riera, A. R., Mendes, J. E. T., da Silva, F. N. F., Yanowitz, F., de Abreu, L. C., Figueiredo, J. L., Raimundo, R. D., Barbosa-Barros, R., Nikus, K., & Brugada, P. (2021) · Journal of Human Growth and Development · doi:10.36311/jhgd.v31.11074 · Cited by 4
Recognition and Clinical Implications of High Prevalence of Migraine in Patients with Brugada Syndrome and Drug-Induced Type 1 Brugada Pattern
Hasdemir, C., Gokcay, F., Orman, M., Kocabaş, U., Payzın, S., Şahin, H., Nyholt, D., & Antzelevitch, C. (2020) · Cardiovascular Electrophysiology · doi:10.1111/jce.14778 · Cited by 4
Self-citation
Brugada Syndrome: A Review
Goit, L. N., & Yang, S.-N. (2019) · Yangtze Medicine · doi:10.4236/ym.2019.34023 · Cited by 4
“These genes only account for small percentage of Brugada syndrome [14].”
Background
Alternative Splicing at N Terminus and Domain I Modulates CaV1.2 Inactivation and Surface Expression.
Bartels, P., Yu, D.-J., Huang, H., Hu, Z., Herzig, S., & Soong, T. (2018) · Biophysical Journal · doi:10.1016/j.bpj.2018.06.001 · Cited by 4
“2 loss of function resulting in ventricular arrhythmia (56).”
BackgroundResult
Ventricular fibrillation followed by the augmentation of Brugada-like electrocardiographic changes caused by ischemia of the conus branch in a patient with coronary artery disease
Nagamoto, Y., Fujii, Y., Morita, Y., Ueda, Y., Yamane, K., Miyake, Y., Fujiwara, M., Mito, S., Watari, Y., Tamekiyo, H., et al. (2017) · doi:10.1016/j.ihjccr.2017.12.003 · Cited by 4
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A1427S missense mutation in scn5a causes type 1 brugada pattern, recurrent ventricular tachyarrhythmias and right ventricular structural abnormalities
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“The QT interval is unusually short in patients with Brugada syndrome who are affected by specific genetic defects (mutations in calcium channel genes), as described below [24].”
Background
Síndrome de Brugada: puesta al día
Heras, R. P. (2013) · Cardiocore · doi:10.1016/j.carcor.2012.10.001 · Cited by 4
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Self-citation

Authors: Antzelevitch, C., Pollevick, G. D., Cordeiro, J. M., Casis, O., Sanguinetti, M. C., Aizawa, Y., Guerchicoff, A., Pfeiffer, R., Oliva, A., Wollnik, B., Gelber, P., Bonaros, E. P., Burashnikov, E., Wu, Y., Sargent, J. D., Schickel, S., Oberheiden, R., Bhatia, A., Hsu, L.-F., Haïssaguerre, M., Schimpf, R., Borggrefe, M., & Wolpert, C.
Affiliations: University of Cologne (DE)
From the Masonic Medical Research Laboratory (C.A., G.D.P., J.M.C., H.A., A.G., R.P., A.O., E.B., Y.W.), Utica, NY; Nora Eccles Harrison Cardiovascular Research and Training Institute (O.C., M.C.S., J.D.S.), University of Utah, Salt Lake City, Utah; Center for Molecular Medicine Cologne (B.W.), Institute of Human Genetics, University of Cologne, Germany; Cardiovascular Consultants of Long Island (P.G., E.P.B.), New Hyde Park, NY; Department of Internal Medicine (S.S., R.O.), Academic Hospital...
ORCID: Antzelevitch, Charles
Cordeiro, Jonathan M.
Sanguinetti, Michael C.
Aizawa, Yoshiyasu
Guerchicoff, Alejandra
Pfeiffer, Ryan
Oliva, Antonio
Wollnik, Bernd
Bhatia, Atul
Borggrefe, Martin
Venue: Circulation
Publisher: Ovid Technologies (Wolters Kluwer Health)
Published: 2007-01-30
Volume: 115
Issue: 4
Pages: 442-449
ISSN: 0009-7322 (ISSN-L)
1524-4539
DOI: 10.1161/circulationaha.106.668392
PMC: PMC1952683
OpenAlex: W2089861793
Cited by: 933
References: 0
Citations by year: 2026: 9 · 2025: 17 · 2024: 22 · 2023: 24 · 2022: 25 · 2021: 35 · 2020: 34 · 2019: 35 · 2018: 47 · 2017: 60 · 2016: 55 · 2015: 51 · 2014: 44 · 2013: 85 · 2012: 82
FWCI: 54.48
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Locations: Circulation (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
GRO (submittedVersion)
Funders: National Heart, Lung, and Blood Institute (R01HL047678)
Topics: Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac electrophysiology and arrhythmias
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Ion channel regulation and function
Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiovascular Effects of Exercise
Keywords: Brugada syndrome, L-type calcium channels, CACNA1C, CACNB2, CACNA2D1, loss-of-function mutations, sudden cardiac death, short QT interval, ST-segment elevation, cardiac ion channelopathy, channel trafficking, quinidine, ventricular tachycardia, familial arrhythmia
MeSH terms: Adult, Animals, Cricetulus, Electrocardiography, Family Health, Female, Cricetinae, Humans, Genetic Linkage, Male, Phenotype, Registries, Ventricular Fibrillation, Calcium Channels, Mutagenesis, Site-Directed, CHO Cells, Death, Sudden, Cardiac, Tachycardia, Ventricular, Patch-Clamp Techniques, Mutation, Missense, Calcium Channels, L-Type, White People

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Loss-of-Function Mutations in the Cardiac Calcium Channel Underlie a New Clinical Entity Characterized by ST-Segment Elevation, Short QT Intervals, and Sudden Cardiac Death

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