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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Background
Coexistent manifestations of the Andersen-Tawil and Brugada syndromes.
Shandling, A. H., & Safani, M. (2008) · Journal of Electrocardiology · doi:10.1016/j.jelectrocard.2007.09.010 · Cited by 2
In Silico Investigation of CACNA2D1 S755T Mutation Associated With Short QT Syndrome
Zhang, S.-G., Lu, W.-G., Yang, F., & Wei, Z.-Q. (2021) · IEEE Access · doi:10.1109/access.2021.3082174 · Cited by 2
“Up to now, totally eight SQTS genotype variants have been recognized [2] and are associated with gain-of-function mutations to K channel genes (SQTS1-3) [3]–[7], loss-of-function mutations to Ca2+ channel genes (SQTS4-6) [8], [9], and mutations to other channel genes including Na (SQTS7)”
Background
Voltage-gated calcium channels in GtoPdb v.2021.2
Catterall, W. A., Perez‐Reyes, E., Snutch, T. P., & Striessnig, J. (2021) · IUPHAR/BPS Guide to Pharmacology CITE · doi:10.2218/gtopdb/f80/2021.2 · Cited by 2
Calcium Channel Splice Variants and Their Effects in Brain and Cardiovascular Function
Yeow, S. Q. Z., Loh, K. W. Z., & Soong, T. W. (2021) · Advances in experimental medicine and biology · doi:10.1007/978-981-16-4254-8_5 · Cited by 4
Ionic and Cellular Mechanisms Underlying J Wave Syndromes
Antzelevitch, C., & Patocskai, B. (2016) · Springer eBooks · doi:10.1007/978-3-319-31578-2_3 · Cited by 2
Self-citation
ST-T Waveform Features, QT and Mortality Risk
Rautaharju, P. (2015) · doi:10.1007/978-3-319-15293-6_9 · Cited by 2
Genomics of cardiac electrical function
Lodder, E. M., & Bezzina, C. R. (2013) · Briefings in Functional Genomics · doi:10.1093/bfgp/elt029 · Cited by 2
Inside Molecular Mechanisms and Pharmacological Targets of Atrial Fibrillation
Scridon, A., & Dobreanu, D. (2013) · Springer eBooks · doi:10.1007/978-1-4471-5475-4_2 · Cited by 1
Channelopathies and Heart Disease
Amuzescu, B. P., Istrate, B. M., & Musat, S. (2013) · Springer eBooks · doi:10.1007/978-1-4471-5316-0_9 · Cited by 2
Muerte súbita en pacientes sin cardiopatía estructural
Benito, B. (2013) · Revista Española de Cardiología Suplementos · doi:10.1016/s1131-3587(13)70062-1 · Cited by 2
Acquired (Drug-Induced) Long and Short QT Syndromes
Shah, R., & Gussak, I. (2013) · Springer eBooks · doi:10.1007/978-1-4471-4978-1_6 · Cited by 2
Comparisons of Substrates Responsible for Atrial Versus Ventricular Fibrillation
Burstein, B., Comtois, P., & Nattel, S. (2008) · Springer eBooks · doi:10.1007/978-1-84628-854-8_17 · Cited by 1
L-type Calcium Channel Disease
Ruan, Y., Bloise, R., Napolitano, C., & Priori, S. G. (2008) · Springer eBooks · doi:10.1007/978-1-84628-854-8_11 · Cited by 1
“Of clinical relevance, it is unclear why gain of function mutations cause the complex phenotype of Timothy syndrome with multi-organ involvements (see below) while loss of function mutations have been associated with Brugada/short QT phenotype with no signs of extra-cardiac disorders [ 2 ] .”
Background
Timothy syndrome and CACNA1C-Related Disorder: first international language and management guidelines consensus statement
Underwood, J. F. G., Timothy, K. W., Tyroll, H., Levy, R. J., Dick, I. E., Pitt, G. S., Tunbridge, E., Baban, A., Wilkinson, G., Hall, N., et al. (2026) · European Journal of Human Genetics · doi:10.1038/s41431-026-02178-8 · Cited by 1
“Finally, we present the ﬁ rst guidelines on standards of diagnostic and clinical care for individuals presenting with a rare CACNA1C gene variant, driven by the evidence that, with appropriate interventions, these individuals can live longer, ful ﬁ lling lives.”
Role of NADPH oxidase 2-derived reactive oxygen species in cardiac electrophysiological disorders
Li, B., Dong, Y., Chen, Y., Liu, C., & Li, Y. (2026) · Channels · doi:10.1080/19336950.2026.2696810
“Loss-of-function mutations in CACNA1C, CACNB2, and CACNA2D1 intrinsically reduce I Ca,L [89,132].”
Risk Stratification in the Short-QT Syndrome: Findings From a Pooled Analysis.
Giladi, M., Solomon, A., Viskin, D., Rosso, R., van der Werf, C., Pinto, S. G., Wilde, A., Elbassel, R., Henriques, L., Bos, J., et al. (2026) · Heart Rhythm · doi:10.1016/j.hrthm.2026.03.001 · Cited by 1
Caenorhabditis elegans as an in vivo model system for human inherited primary arrhythmia syndromes.
Delinière, A., Boulin, T., Jospin, M., Janin, A., Millat, G., Chevalier, P., & Andrini, O. (2025) · Journal of Physiology · doi:10.1113/jp289661 · Cited by 1
Short QT Syndrome and Drug Treatment: A systematic Literature Review and PRISMA Analysis
You, T., Luo, C.-J., Zhang, K., & Zhang, H.-G. (2025) · International Journal of Drug Discovery and Pharmacology · doi:10.53941/ijddp.2025.100009 · Cited by 1
“…associated with SQT4 have been reported, including: (1) G490R, which is associated with a poor rate dependence and ST segment elevation in the ECG [41]; (2) A39V, which is associated with apparent ST elevation in V1 and saddleback ST elevation in V2 [41]; (3) R1937P, which is associated with an…”
Influential
The membrane-associated β2e-subunit of voltage-gated calcium channels translocates to the nucleus and regulates gene expression
Miranda-Laferte, E., Barkovits, K., Rozanova, S., Jordan, N., Marcus, K., & Hidalgo, P. (2025) · Frontiers in Physiology · doi:10.3389/fphys.2025.1555934 · Cited by 1
Differential effects of MATR3 variants on its cryptic splicing repression function
Khan, M., Chen, X. X. L., Dias, M., Santos, J. R., Kour, S., You, J., van Bruggen, R., Youssef, M. M. M., Wan, Y.-W., Liu, Z.-D., et al. (2023) · bioRxiv · doi:10.1101/2023.12.07.570685 · Cited by 1
“…and stabilization [63] CACNB2 Between exon 9 and 10 Encodes the calcium voltage-gated channel auxiliary subunit beta 2 [64] Brugada syndrome [80] UHRF2 Between exon 4 and 5 Encodes the ubiquitin-like, containing PHD and RING finger domains 2 protein; involved in DNA demethylation and plays…”
Background
Cav1.4 congenital stationary night blindness is associated with an increased rate of proteasomal degradation
Sadeh, T., Baines, R., Black, G. C. M., & Manson, F. D. C. (2023) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2023.1161548 · Cited by 1
“Pathogenic variation of all four Cav1 channels is associated with human diseases across a wide range of pathologies, including cardiovascular (Antzelevitch et al., 2007), neurological (Tumienė et al.”
Background
Frontier and hotspot evolution in Brugada syndrome: A bibliometric analysis from 2002 to 2022
Liu, S., Xia, H., Yao, X., Liu, H., Liu, Y., Xia, X.-D., Wang, D., Liu, X., & Li, G. (2023) · Medicine · doi:10.1097/md.0000000000033038 · Cited by 1
“2, BrS3) and CACNB2b (Cavβ2b, BrS4) by Antzelevitch et al in 2007.[33] In 2008, Deplón et al[34] first described KCNE3 (MiRP2, BrS6) which regulates the potassium channel Ito associated with BrS.”
Inherited Ventricular Arrhythmias, the Channelopathies and SCD; Current Knowledge and Future Speculation – Epidemiology and Basic Electrophysiology
Abdulgader, A. A. A. (2020) · IntechOpen eBooks · doi:10.5772/intechopen.92073 · Cited by 1
Drug-Induced Brugada Syndrome in a Psychiatric Patient: a Case Report
Ottaviani, C., Luciani, M., Bentivegna, E., Spuntarelli, V., Salemi, S., Rosa, R. D. D., & Martelletti, P. (2019) · SN Comprehensive Clinical Medicine · doi:10.1007/s42399-019-00097-y · Cited by 1
Intraoperative Sudden Cardiac Death In Pediatric Patients - Calamity yet to Overcome?
Annachhatre, A. (2019) · Annals of Cardiac Anaesthesia · doi:10.4103/aca.aca_90_18 · Cited by 1
“Brugada syndrome: This syndrome occurs because of genetic mutation in sodium channel.[10] Sudden cardiac death in this syndrome is 4% under 40 years of age.”
Background
Channelopathies in Heart Disease
Remme, C., & Thomas, D. (2018) · Cardiac and Vascular Biology · doi:10.1007/978-3-319-77812-9 · Cited by 1
“Short QT intervals, but in the context of an overall Brugada syndrome phenotype, have been described due to mutations in the genes encoding the α and β2 subunits of the cardiac Ca channel, but these most likely form part of a distinct clinical entity (Antzelevitch et al. 2007).”
When High Throughput Meets Mechanistic Studies: A State-of-the-Art Approach in Brugada Syndrome.
Heidecker, B. (2017) · Circulation Research · doi:10.1161/circresaha.117.311543 · Cited by 1
“Furthermore, mutations of the L-type calcium channel α1, β2, and α2δ subunits encoded by CACNA1, CACNB2B, and CACNA2B are estimated to cause 10% to 15% of Brugada syndrome.(10,11) Functional analyses have shown that mutations in BrS genes result in the reduction of the cardiac sodium (I Na ) current, increase in the t…”
Background
An Inherited Arrhythmia Syndrome with Long QT, Sudden Death and Depolarization Disorder Due to an In-Frame Deletion in Exon 16 of the CACNA1C Gene
Rafiq, M., Koopmann, T., Zahavich, L., Fatah, M., & Hamilton, R. (2017) · doi:10.4172/2469-9853.1000144 · Cited by 1
Brugada syndrome and calcium channel mutation in a patient with congenital deaf mutism
Canpolat, U., Çoteli, C., & Aytemir, K. (2017) · Indian Pacing and Electrophysiology Journal · doi:10.1016/j.ipej.2017.01.002 · Cited by 1
“2a1) may cause Timothy and Brugada syndromes [7,8].”
Background
Effects of propafenone on KCNH2-linked short QT syndrome: A modelling study
Luo, C.-J., Wang, K.-Q., & Zhang, H.-G. (2016) · IEEE International Conference on Bioinformatics and Biomedicine · doi:10.1109/bibm.2016.7822744 · Cited by 1
Rare Disease and Low Event Rates: Challenges for Refining Risk Stratification in Brugada Syndrome.
Roberts, J. D., & Klein, G. (2016) · Canadian Journal of Cardiology · doi:10.1016/j.cjca.2016.02.050 · Cited by 1
A 33-year-old man after sudden cardiac arrest as a first manifestation of Brugada syndrome
Holcman, K., Rubis, P., Wiśniowska-Śmiałek, S., Biernacka-Fiałkowska, B., Hlawaty, M., Leśniak-Sobelga, A., Karkowski, G., Bednarek, J., Lelakowski, J., Kostkiewicz, M., et al. (2016) · doi:10.20418/jrcd.vol2no7.221 · Cited by 1
“In patients with clinical diagnosis of Brugada syn‐ drome mutations in the alpha and beta subunits of the calcium channel gene also have been found [16].”
Background
Genetic and clinical aspects of brugada syndrome
Banu, L., & Najnin, R. (2015) · doi:10.5530/ami.2015.4.2 · Cited by 1
MOLECULAR ALTERATIONS IN HUMAN GENETIC DISEASES THROUGH NEXT GENERATION SEQUENCING TECHNOLOGIES
D'Argenio, V. (2015) · doi:10.6092/unina/fedoa/10057 · Cited by 1
“With the caveat that the role of these two CACNA1C should be verified in functional assays, it is conceivable that, by modifying intracellular calcium concentration [151], the variant protein could impair myocyte contractility, which in turn could lead to ventricular”
BackgroundResult
Ionenkanalerkrankungen: Schnittstellen zwischen Kardiomyopathien und malignen Arrhythmien
Schimpf, R., Rudic, B., Tülümen, E., Papavassiliu, T., Dösch, C., & Borggrefe, M. (2013) · Deutsche Medizinische Wochenschrift · doi:10.1055/s-0032-1332973 · Cited by 1
Self-citation
Syndrome du QT long congénital, tachycardie ventriculaire catécholergique, syndrome de Brugada et mort subite inexpliquée en pédiatrie
Denjoy, I., Maltret, A., & Probst, V. (2012) · Archives of Cardiovascular Diseases Supplements · doi:10.1016/s1878-6480(12)70829-7 · Cited by 1

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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