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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
Open accessAbstract
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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“Short QT syndrome KCNH2 KCNQ1 KCNJ2 CACNA1C CACNB2b IKr IKs IK1 ICa ICa Up to 70% 853, 856-858”
From 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS (2016) · cites this paper as [853]
In the citing paper
“Brugada syndrome SCN5A GPDIL SCN1B CACNA1C CACNB2b others INa INa INa ICa ICa others 10-20% 851-855”
From 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS (2016) · cites this paper as [853]
In the citing paper
“AF prevalence ranges from 5% to 20% in patients with long QT syndrome or Brugada syndrome, and is up to 70% in short QT syndrome (Table 20).853,[856][857][858]”
From 2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS (2016) · cites this paper as [853]
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J-Wave syndromes expert consensus conference report: Emerging concepts and gaps in knowledge.
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“The QT interval is relatively short in patients with ERS [2,113], and BrS who carry mutations in calcium channel genes [114].”
BackgroundSelf-citationJuang, J., & Horie, M. (2016) · Journal of Arrhythmia · doi:10.1016/j.joa.2016.07.012 · Cited by 153
L-type calcium channel targeting and local signalling in cardiac myocytes.
Shaw, R., & Colecraft, H. M. (2013) · Cardiovascular Research · doi:10.1093/cvr/cvt021 · Cited by 150
Short QT Syndrome: From Bench to Bedside
Patel, C., Yan, G.-X., & Antzelevitch, C. (2010) · Circulation: Arrhythmia and Electrophysiology · doi:10.1161/circep.109.921056 · Cited by 150
Self-citationThe hERG K+ channel: target and antitarget strategies in drug development
Raschi, E., Vasina, V. I., Poluzzi, E., & Ponti, F. D. (2008) · Pharmacological Research · doi:10.1016/j.phrs.2008.01.009 · Cited by 146
“[23] Antzelevitch C, Pollevick GD, Cordeiro JM, Casis O, Sanguinetti MC,”
BackgroundBrugada syndrome: clinical and genetic findings
Sarquella-Brugada, G., Campuzano, Ó., Arbelo, E., Brugada, J., & Brugada, R. (2015) · Genetics in Medicine · doi:10.1038/gim.2015.35 · Cited by 143
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Precision medicine and therapies of the future
Sisodiya, S. (2020) · Epilepsia · doi:10.1111/epi.16539 · Cited by 139
J Wave syndromes: Brugada and Early Repolarization Syndromes
Antzelevitch, C., & Yan, G.-X. (2015) · Heart Rhythm · doi:10.1016/j.hrthm.2015.04.014 · Cited by 139
Self-citationCardiac Channelopathies and Sudden Death: Recent Clinical and Genetic Advances
Fernández-Falgueras, A., Sarquella‐Brugada, G., Brugada, J., Brugada, R., & Campuzano, Ó. (2017) · Biology · doi:10.3390/biology6010007 · Cited by 146
“5% of BrS cases in which patients present with a syndrome overlapping the typical BrS ECG pattern with a short QT interval [37,38].”
BackgroundDrug-induced Brugada syndrome.
Yap, Y., Behr, E., & Camm, A. (2009) · Europace · doi:10.1093/europace/eup114 · Cited by 135
“loss-of-function missense mutations in CACNA1C (A39V and G490R) and CACNB2 (S481L) encoding the a1- and b2b-subunits of the L-type calcium channel have been found to be the underlying cause.(5) Similarly, a mutation in the glycerol-3-phosphate dehydrogenase 1-like (GPD1-L) gene has also been identified as a less commo…”
BackgroundIon Channel Macromolecular Complexes in Cardiomyocytes: Roles in Sudden Cardiac Death
Abriel, H., Rougier, J., & Jalife, J. (2015) · Circulation Research · doi:10.1161/circresaha.116.305017 · Cited by 133
“S481L) of the CACNB2 gene, encoding the Ca v β2 subunit, was found in a BrS patient.(71) Despite the large I Ca mutation-induced decrease in heterologous expression systems, no reduction of Ca V 1.”
BackgroundSzél, T., & Antzelevitch, C. (2014) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2014.01.067 · Cited by 133
“Discussion It is well established that mutations leading to a decrease in inward currents (INa or ICaL) or increase in outward currents (Ito and IK-ATP) are capable of causing BrS in humans (5,19-22).”
BackgroundSelf-citationGargus, J. J. (2008) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2008.03572.x · Cited by 134
Lu, H.-R., Vlaminckx, E., Hermans, A. N., Rohrbacher, J., van Ammel, K., Towart, R., Pugsley, M., & Gallacher, D. (2008) · British Journal of Pharmacology · doi:10.1038/bjp.2008.191 · Cited by 131
“, 2005) as well as ‘loss-of-function’ mutations in genes encoding the cardiac L-type calcium channel (Antzelevitch et al., 2007) have been associated to date with the congenital short QT syndrome.”
BackgroundKoncz, I., Gurabi, Z., Patocskai, B., Panama, B. K., Szél, T., Hu, D., Barajas-Martinez, H., & Antzelevitch, C. (2013) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2013.12.012 · Cited by 130
Self-citationCardiac channelopathies: Genetic and molecular mechanisms
Abriel, H., & Zaklyazminskaya, E. V. (2012) · Gene · doi:10.1016/j.gene.2012.12.061 · Cited by 118
Genetics of sudden death: focus on inherited channelopathies.
Cerrone, M., & Priori, S. (2011) · European Heart Journal · doi:10.1093/eurheartj/ehr082 · Cited by 128
Ohno, S., Zankov, D., Ding, W.-G., Itoh, H., Makiyama, T., Doi, T., Shizuta, S., Hattori, T., Miyamoto, A., Naiki, N., et al. (2011) · Circulation: Arrhythmia and Electrophysiology · doi:10.1161/circep.110.959619 · Cited by 128
Defects in Ankyrin-Based Membrane Protein Targeting Pathways Underlie Atrial Fibrillation
Cunha, S. R., Hund, T. J., Hashemi, S., Voigt, N., Li, N., Wright, P., Koval, O. M., Li, J., Gudmundsson, H., Gumina, R. J., et al. (2011) · Circulation · doi:10.1161/circulationaha.111.023986 · Cited by 111
Myokit: A simple interface to cardiac cellular electrophysiology
Clerx, M., Collins, P. J., de Lange, E., & Volders, P. G. A. (2015) · Progress in Biophysics and Molecular Biology · doi:10.1016/j.pbiomolbio.2015.12.008 · Cited by 132
“A pathological case was created by reducing cell-to-cell conductance, decreasing gCaL to 50% (Antzelevitch et al., 2007), increasing epicardial and midmyocardial gTo to 250% and adding a shift in ITo voltage dependence.”
MethodQT-Interval Duration and Mortality Rate
Zhang, Y.-Y., Post, W., Dalal, D., Blasco-Colmenares, E., Tomaselli, G., & Guallar, E. (2011) · Archives of Internal Medicine · doi:10.1001/archinternmed.2011.433 · Cited by 126
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Cordeiro, J., Marieb, M. A., Pfeiffer, R., Calloe, K., Burashnikov, E., & Antzelevitch, C. (2009) · Journal of Molecular and Cellular Cardiology · doi:10.1016/j.yjmcc.2009.01.014 · Cited by 122
Self-citationAtrial fibrillation and Brugada syndrome.
Francis, J., & Antzelevitch, C. (2008) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2007.10.062 · Cited by 121
“Mutations in he and subunits of the calcium channel can also lead to shorter than normal QT interval, creating a new clinical ntity consisting of a combined Brugada/short-QT synrome (3).”
BackgroundInfluentialSelf-citationCalloe, K., Cordeiro, J., Diego, J. D. D., Hansen, R., Grunnet, M., Olesen, S., & Antzelevitch, C. (2008) · Cardiovascular Research · doi:10.1093/cvr/cvn339 · Cited by 120
“Our new experimental model of BrS also recapitulates the clinical finding that a slight increase in QT interval is observed in the right precordial leads in association with ST-segment elevation in some BrS patients.(6) Our model shows that the prolongation of APD90 in the epicardium is Figure 7 Effect of NS5806 to in…”
Self-citationHuman ether-a-go-go related gene (hERG) K+ channels: Function and dysfunction
Perrin, M. J., Subbiah, R. N., Vandenberg, J. I., & Hill, A. P. (2008) · Progress in Biophysics and Molecular Biology · doi:10.1016/j.pbiomolbio.2008.10.006 · Cited by 115
Channelopathy pathogenesis in autism spectrum disorders
Schmunk, G., & Gargus, J. J. (2013) · Frontiers in Genetics · doi:10.3389/fgene.2013.00222 · Cited by 126
“This is supported by the finding that the two missense alleles at this locus that cause the short QT Brugada syndrome, A39V and G490R, are loss-of-function lesions (Antzelevitch et al., 2007; Brugada et al., 2012).”
BackgroundBrugada Syndrome: Clinical, Genetic, Molecular, Cellular, and Ionic Aspects.
Antzelevitch, C., & Patocskai, B. (2016) · Current problems in cardiology · doi:10.1016/j.cpcardiol.2015.06.002 · Cited by 118
Self-citationCardiomyopathic and channelopathic causes of sudden unexplained death in infants and children.
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Structure and function of the β subunit of voltage-gated Ca2+ channels
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Empiric quinidine therapy for asymptomatic Brugada syndrome: Time for a prospective registry
Viskin, S., Wilde, A., Tan, H. L., Antzelevitch, C., Shimizu, W., & Belhassen, B. (2008) · Heart Rhythm · doi:10.1016/j.hrthm.2008.11.030 · Cited by 114
Self-citationChahal, C., Salloum, M. N., Alahdab, F., Gottwald, J. A., Tester, D., Anwer, L. A., So, E. L., Murad, M., Louis, E. S. S., Ackerman, M., et al. (2019) · Journal of the American Heart Association : Cardiovascular and Cerebrovascular Disease · doi:10.1161/jaha.119.012264 · Cited by 109
“Likely deleterious variants in 373 genes were identified exclusively in the SUDEP group, 1 of which was CACNB2 associated with BrS (the exact variant is not reported and is predicted by in silico modeling only).(52,53) Other than the known SCN1A pathogenic variants in DS Figure 2.”
BackgroundFGF12 is a candidate Brugada syndrome locus
Hennessey, J. A., Marcou, C. A., Wang, C., Wei, E. Q., Wang, C.-J., Tester, D., Torchio, M., Dagradi, F., Crotti, L., Schwartz, P., et al. (2013) · Heart Rhythm · doi:10.1016/j.hrthm.2013.09.064 · Cited by 109
Benito, B., Guasch, E., Rivard, L., & Nattel, S. (2010) · Journal of the American College of Cardiology · doi:10.1016/j.jacc.2010.05.037 · Cited by 107
CaV1.2 channelopathies: from arrhythmias to autism, bipolar disorder, and immunodeficiency
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“2 channelopathy, a subsequent study of Brugada syndrome patients revealed a loss-of-function phenotype in either the pore-forming α1 subunit or the auxiliary β subunit [4].”
Modeling Short QT Syndrome Using Human‐Induced Pluripotent Stem Cell–Derived Cardiomyocytes
El‐Battrawy, I., Lan, H., Cyganek, L., Zhao, Z., Li, X., Buljubasic, F., Lang, S., Yücel, G., Sattler, K., Zimmermann, W., et al. (2018) · Journal of the American Heart Association · doi:10.1161/jaha.117.007394 · Cited by 120
“Additionally, overlap syndrome, SQTS with Brugada syndrome, has been reported.(12,13) Causes of acquired SQTS are electrolyte imbalance including hyperkalemia or hypercalcemia, myocardial ischemia, acidosis, or carnitine deficiency.”
BackgroundSelf-citation
Metadata
- 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
- Venue
- Circulation
- Published
- 2007-01-30
- Volume
- 115
- Issue
- 4
- Pages
- 442-449
- ISSN
- 0009-7322 (ISSN-L)
- 1524-4539
- 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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