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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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“The subtypes SQTS1, SQTS2, and SQTS3 are caused by gainof-function mutations in potassium channel genes KCNQ1, KCNH2, and KCNJ2,(120,122,123) which are also linked to LQTS2, LQTS1, and LQTS7, respectively, whereas SQTS4, SQTS5, and SQTS6 subtypes are caused by loss-of-function mutations in calcium channel genes and ca…”
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“Patients with calcium channel gene mutations have a short QT interval [19].”
BackgroundECG interpretation in Brugada syndrome
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“However, a shorter-than-normal QT interval is less frequently recognized in patients displaying ST-segment elevation in leads V1–V3, which is associated with mutations in genes encoding the cardiac L-type calcium channel [22].”
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“42 The first BrS patients described in the literature as carriers of mutations in the CACNA1c and CACNB2 genes presented with a distinctive phenotype combining short QT interval and type I BrS ECG pattern.”
Long QT Syndromes: Genetic Basis
Schulze‐Bahr, E. (2012) · Cardiac Electrophysiology Clinics · doi:10.1016/j.ccep.2012.01.001 · Cited by 8
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“Missense mutations within CACNB2 have been implicated in Brugada syndrome (Antzelevitch et al., 2007), a rare autosomal dominant disorder that results in idiopathic ventricular fibrillation (London et al., 2007).”
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β subunits of voltage-gated calcium channels in cardiovascular diseases
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J Wave Syndromes: A Decade of Progress
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“Other mutations associated with the Brugada syndrome reduce the L-type calcium current (I CaL) and are located in CACNA1C, CACNB2b (Antzelevitch et al., 2007) and CACNA2D1 (Burashnikov et al., 2010) which encode the α1-, β2b-, and α2δ-subunit of the L-type calcium channel.”
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Images in cardiovascular medicine. Yew causes brugada ECG.
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“Wie kürzlich gezeigt wurde, können darüber hinaus Veränderungen der Calciumkanäle und damit gestörte Calciumströme unter gewissen Bedingungen zu einer Verkürzung der QT-Zeit führen [2, 23].”
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“gene mutations such as CACNA1c [4], CACNB2b [4], GPD1-L [5], SCN1B [6], and KCNE3 [7] have also been reported.”
BackgroundMechanisms of Cardiac Arrhythmia
Antzelevitch, C. N., Burashnikov, A., & Diego, J. M. D. (2008) · Springer eBooks · doi:10.1007/978-1-84628-854-8_6 · Cited by 4
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“Mutations in α1c ( CACNA1C ), β2 ( CACNB2 ) and α2δ ( CACNA2D1 ) are detected in 2–4% of patients with BrS 15,43,68 and result in reduced channel transport during phase 2 and shortened repolarization 43 .”
The Role of Human-Induced Pluripotent Stem Cells in Studying Cardiac Channelopathies
Begovic, M., Schneider, L., Zhou, X., Hamdani, N., Akın, İ., & El‐Battrawy, I. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms252212034 · Cited by 9
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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