CLINICAL RESEARCH: CARDIAC RHYTHM DISORDER
High Risk for Bradyarrhythmic Complications in Patients With Brugada Syndrome Caused by SCN5A Gene Mutations
Takeru Makiyama, MD*,
Masaharu Akao, MD, PhD*,
Keiko Tsuji, BS*,
Takahiro Doi, MD*,
Seiko Ohno, MD*,
Kotoe Takenaka, MD, PhD*,
Atsushi Kobori, MD, PhD*,
Tomonori Ninomiya, MD, PhD*,
Hidetada Yoshida, MD, PhD*,
Makoto Takano, MD, PhD ,
Naomasa Makita, MD, PhD ,
Fumiko Yanagisawa, MD ,
Yukei Higashi, MD, PhD,
Youichi Takeyama, MD, PhD,
Toru Kita, MD, PhD* and
Minoru Horie, MD, PhD||,*
* Department of Cardiovascular Medicine, Kyoto University Graduate School of Medicine, Kyoto, Japan
Division of Biophysics, Department of Physiology, Jichii Medical School, Tochigi, Japan
Department of Cardiovascular Medicine, Hokkaido University Graduate School of Medicine, Sapporo, Japan
Division of Cardiology, Showa University Fujigaoka Hospital, Yokohama, Japan
|| Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Otsu, Japan.
Manuscript received February 23, 2005;
revised manuscript received July 29, 2005,
accepted August 1, 2005.
* Reprint requests and correspondence: Dr. Minoru Horie, Department of Cardiovascular and Respiratory Medicine, Shiga University of Medical Science, Seta Tsukinowa-cho, Otsu, Shiga, 520-2192, Japan. (Email: horie{at}belle.shiga-med.ac.jp).
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Abstract
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OBJECTIVES: We carried out a complete screening of the SCN5A gene in 38 Japanese patients with Brugada syndrome to investigate the genotype-phenotype relationship.
BACKGROUND: The gene SCN5A encodes the pore-forming  -subunit of voltage-gated cardiac sodium (Na) channel, which plays an important role in heart excitation/contraction. Mutations of SCN5A have been identified in 15% of patients with Brugada syndrome.
METHODS: In 38 unrelated patients with clinically diagnosed Brugada syndrome, we screened for SCN5A gene mutations using denaturing high-performance liquid chromatography and direct sequencing, and conducted a functional assay for identified mutations using whole-cell patch-clamp in heterologous expression system.
RESULTS: Four heterozygous mutations were identified (T187I, D356N, K1578fs/52, and R1623X) in 4 of the 38 patients. All of them had bradyarrhythmic complications: three with sick sinus syndrome (SSS) and the other (D356N) with paroxysmal complete atrioventricular block. SCN5A-linked Brugada patients were associated with a higher incidence of bradyarrhythmia (4 of 4) than non–SCN5A-linked Brugada patients (2 of 34). Families with T187I and K1578fs/52 had widespread penetrance of SSS. Notably, the patient with K1578fs/52, who had been diagnosed as having familial SSS without any clinical signs of Brugada syndrome, showed a Brugada-type ST-segment elevation after intravenous administration of pilsicainide and programmed electrical stimulation-induced ventricular tachycardia. All of the mutations encoded non-functional Na channels, and thus were suggested to cause impulse propagation defect underlying bradyarrhythmias.
CONCLUSIONS: Our findings suggest that loss-of-function SCN5A mutations resulting in Brugada syndrome are distinguished by profound bradyarrhythmias.
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Abbreviations and Acronyms
| | AVB = atrioventricular block | | DHPLC = denaturing high-performance liquid chromatography | | hß1 = human ß1-subunit | | PCCD = progressive cardiac conduction defect | | SSS = sick sinus syndrome | | VF = ventricular fibrillation | | VT = ventricular tachycardia |
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Brugada syndrome is an inherited disorder, characterized by sudden death from ventricular tachyarrhythmias especially during sleep, ST-segment elevation in the right precordial leads, and conduction slowing in the absence of structural heart disease (1,2). In approximately 15% of Brugada patients, mutations of the SCN5A gene, which encodes the pore-forming -subunit of voltage-gated cardiac sodium (Na) channel, have been identified, and functional analyses for some of these mutations revealed a loss-of-function type modulation (3–6). Because Na current plays a key role in heart excitation/contraction, functional changes in these channels can cause a variety of cardiac phenotypes. Interestingly, mutations of SCN5A have been reported to generate several types of disease entities distinct from Brugada syndrome: congenital type 3 long-QT syndrome (7), idiopathic ventricular fibrillation (VF) (8), progressive cardiac conduction defect (PCCD) (9), congenital sick sinus syndrome (SSS) (10), atrial fibrillation (11), and even overlap syndrome (12,13).
In this study, we carried out a complete screening of the SCN5A gene in 38 Japanese Brugada patients to investigate the genotype-phenotype relationship.
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Methods
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Study subjects.
This study enrolled 38 clinically diagnosed Japanese Brugada syndrome patients (all were unrelated probands). The protocol for genetic analysis was approved by the institutional ethics committee and was performed under its guidelines. All patients provided an informed consent before the genetic analysis. The diagnosis of Brugada syndrome was based on the presence of ST-segment elevation  2 mm in leads V1 through V3 at baseline or after administration of intravenous Na channel blockers (e.g., pilsicainide) (14). The presence of right ventricular cardiomyopathy was excluded by echocardiography. We defined diagnosis of SSS as having a documented sinus pause 3 s or chronic sinus bradycardia with a heart rate <50 beats/min.
Deoxyribonucleic acid isolation and mutation analysis.
The methods of DNA isolation and mutation analysis were described elsewhere (15). Genetic screening was performed for SCN5A by denaturing high-performance liquid chromatography (DHPLC) using a WAVE System Model 3500 (Transgenomic, Omaha, Nebraska).
Site-directed mutagenesis and electrophysiology.
With regard to the novel SCN5A mutations we identified, site-directed mutagenesis was employed to construct mutants (15). The human cell line HEK293 was transiently transfected with either wild-type human cardiac Na channel subunit (hH1) or mutant cDNA by the LipofectAMINE method according to the manufacturer’s instructions (Invitrogen, Carlsbad, California) in combination with a bicistronic plasmid (pEGFP-IRES-hß1) encoding enhanced green fluorescent protein and the human ß1-subunit (hß1) to visually identify cells expressing heterologous hß1.
Sodium currents were recorded 24 to 48 h after transfection using the whole-cell patch-clamp technique and analyzed, as we previously described (15). Functional expression studies were performed on multiple independent recombinants.
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Results
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Mutation analysis.
Table 1 shows clinical characteristics of 38 patients with Brugada syndrome enrolled in this study (35 men/3 women, 20 symptomatic/18 asymptomatic, mean age 47.4 ± 17.0 years). A total of 35 probands were already documented with Brugada-type ST-segment elevation at rest (19 symptomatic/16 asymptomatic). The others (three probands) displayed ST-segment elevation after intravenous administration of pilsicainide. Of 18 asymptomatic Brugada patients, 16 underwent programmed electrical stimulation and 15 of them displayed ventricular tachycardia (VT) or VF. Five patients were associated with SSS.
We identified four heterozygous SCN5A mutations in four unrelated patients: T187I (c559t), D356N (g1066a), K1578fs/52 (4729 aa insertion), and R1623X (c4864t). Figure 1 shows the positions of identified mutations. K1578fs/52 is a frame-shift mutation resulting in early truncation of the channel protein. R1623X is a nonsense mutation that changes an arginine for a stop codon. The results of DHPLC and DNA sequencing were presented in Figure 2. Three (T187I, D356N, K1578fs/52) were novel and the other (R1623X) was reported to cause congenital SSS in combination with T220I (10). None of these mutations was found in 110 normal control individuals (220 chromosomes). Consistent with a previous report (4), the incidence of SCN5A mutations in the Brugada syndrome patients we studied was approximately 10% (4 of 38).
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Figure 1 Topology of the voltage-gated sodium (Na) channel. Scheme of the transmembrane topology of the cardiac Na channel illustrating the location of four mutations found in our study. The cardiac Na channel -subunit consists of four domains (DI through DIV), each containing six transmembrane-spanning segments.
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Figure 2 Denaturing high-performance liquid chromatography (DHPLC) analysis and deoxyribonucleic acid (DNA) sequencing. (Top panels of A through D) DHPLC confirms abnormal migration patterns in the affected individuals. (Bottom panels of A through D) Automated DNA sequencing electropherograms demonstrate mutations in each proband.
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Clinical features.
Family K-115 (T187I)
The proband, a 33-year-old man, in the family K-115 experienced syncope in his febrile state, and VF was documented. His electrocardiogram (ECG) at rest displayed a typical Brugada syndrome pattern (Fig. 3A, left). After the implantation of a cardioverter-defibrillator, he showed sinus bradyarrhythmia with occasional ventricular pacing (second beat in Fig. 3A, right), indicating the complication of SSS. His affected mother also suffered from SSS and underwent a pacemaker implantation (Fig. 4A).
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Figure 3 Electrocardiogram (ECG) recordings. (A through D) ECG recordings (V1 through V3) obtained from the probands. (Bottom panel of C) Programmed electrical stimulation (S1-S1/S1-S2/S2-S3/S3-S4 = 600/280/260/240 [ms]) at the right ventricular outflow tract induced monomorphic ventricular tachycardia.
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Figure 4 (A through D) Pedigrees are shown. Circles represent female subjects and squares represent male subjects. The arrowhead indicates the proband. Diagonal bars indicate deceased family members. Members carrying the mutation are represented by solid circles or solid squares. Further explanation is given in the figure. AVB = atrioventricular block; BS = Brugada syndrome; PM = patients with a pacemaker; SSS = sick sinus syndrome.
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Family K-54 (D356N)
The proband, a 62-year-old man, in the family K-54 had recurrent syncope at age 61. He showed a coved-type ST-segment elevation in the right precordial leads (Fig. 3B), and VF was induced when he underwent an electrophysiological study. During hospitalization, a complete atrioventricular block (AVB) was recorded when he experienced faintness. He had no family history of lethal arrhythmia or sudden cardiac death (Fig. 4B). His family members refused genetic examinations.
Family K-202 (K1578fs/52)
A 68-year-old man (III-6, Fig. 4C) who had received a pacemaker (AAI pacing) due to SSS at age 52 experienced repetitive syncope. His ECG on admission showed a severe sinus arrest because of pacemaker pacing and sensing failure. Three members of his family (III-4, III-7, and IV-1) also suffered from SSS and received a pacemaker, and one affected brother (III-2) had first-degree AVB. One of them, a younger sister (III-7) of the proband, died suddenly even after the pacemaker implantation. In order to assess the association with cardiac Na channelopathies, the proband underwent a pilsicainide challenge test. Intravenous pilsicainide (30 mg) produced a marked prolongation of the PQ interval (240 ms  320 ms) and revealed a typical Brugada-type ST-segment elevation in the right precordial leads (Fig. 3C, upper panels). Electrophysiological study induced monomorphic VT (Fig. 3C, lower panel). Then he was diagnosed as having Brugada syndrome along with SSS and subsequently received an implantable cardioverter-defibrillator.
Family K-185 (R1623X)
The proband was a 65-year-old man who experienced recurrent syncope due to sinus arrest for >5 s at age 61 years and received a pacemaker. At age 65 years, he had faintness due to VF at night and was successfully resuscitated by electric defibrillation. His ECG showed a coved-type ST-segment elevation in the precordial leads (Fig. 3D). His family members refused an ECG and genetic analyses.
Functional analysis of SCN5A T187I, D356N, K1578fs/52, and R1623X.
We performed biophysical assays for the four novel mutations using a heterologous expression system in HEK293 cells. The protocol is given schematically in Figure 5. Figure 5A illustrates representative whole-cell current traces from cells expressing wild-type (WT), T187I, D356N, K1578fs/52, or R1623X Na channels in the presence of the coexpressed hß1. None of the mutants showed an inward Na current, indicating that all of the mutations were non-functional. Reportedly, incubation with mexiletine rescued the reduced current density of a mutant Na channel (M1766L) (16). We, therefore, incubated transfected cells in medium containing 500 µmol/l mexiletine, but failed to rescue the expression of these mutants (data not shown).
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Figure 5 Biophysical assay. (A) Whole-cell current recordings of wild-type (WT) and mutant sodium (Na) channels. Sodium channels were expressed with transient transfection in HEK293 cells in the presence of hß1. Currents were recorded at various membrane potentials from –90 to +90 mV in 10-mV increments from a holding potential of –120 mV. No currents were detected in cells expressing each mutant. (B) Voltage dependence of steady-state inactivation and activation of mutant Na channels cotransfected with WT (mutant-hH1 [or pRcCMV as a control to adjust the total amount of DNA]: WT-hH1: hß1 = 1:1:1). The curve was fit with the Boltzmann equation: I/Imax = [1+exp((V-V1/2)/k)–1]. (C) Current densities of mutant Na channels. Na currents were elicited at –30 mV from a holding potential of –120 mV. hH1 = human cardiac Na channel -subunit.
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The four mutations were all heterozygous. To assess the functional interaction between WT and mutant Na channels, we coexpressed the same amount of both plasmids in combination with hß1 in HEK293 cells. Figures 5B and 5C show voltage-dependence of steady-state inactivation/activation and the peak currents. None of the mutants changed channel open probability or current densities, suggesting that the mutants have no dominant-negative effect on WT channels.
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Discussion
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In this report, we identified four loss-of-function SCN5A mutations, T187I, D356N, K1578fs/52, and R1623X in 38 consecutive, unrelated cases of Brugada syndrome in Japan. All four probands were complicated with bradyarrhythmia, such as SSS or AVB. None of these probands had additional SCN5A mutations, suggesting that this type of "loss-of-function" overlap syndrome (Brugada syndrome plus SSS/AVB) may result from a single SCN5A mutation; SSS was documented in 5 of 38 Brugada patients (Table 1), and SCN5A mutations were found in more than half of these five patients (3 of 5), indicating that the patients with the overlap syndrome had a high probability of SCN5A mutations.
In patients with Brugada syndrome, several dozen SCN5A mutations have been reported to date, and the functional analysis of these mutations revealed a "loss-of-function" type modulation of the -subunit of Na channels. The severity of channel dysfunction can be variable in terms of channel conductance or gating properties, depending on the types of mutation. Importantly, as shown in Figure 5A, all of the mutations that we identified in the present study were entirely non-functional, and had no dominant-negative effect on WT channels. This complete suppression of Na channel function may be associated with the profound conduction disturbance, and thus bradyarrhythmic phenotypes.
The loss-of-function type mutations of SCN5A are reportedly responsible for not only Brugada syndrome but also PCCD (9,17,18), congenital SSS (10), and overlap syndrome (Brugada syndrome plus atrial standstill or sinus node dysfunction) (19,20), supporting the concept that Brugada syndrome and its bradyarrhythmic complications are caused by a single SCN5A mutation. The cellular mechanism for bradyarrhythmias is either a slowing of pacemaker activity or a reduction in impulse propagation. The former seems to be unlikely, because the pacemaker current in sinus nodal cells is largely regulated by calcium and potassium channels, with a minor contribution of Na channels (21,22). Sodium channels in the center of the mouse sinus node consist of tetrodotoxin-sensitive brain-type -subunits, not tetrodotoxin-insensitive heart-type -subunits encoded by Scn5a, a mouse homologue of SCN5A (23). In addition, however, Scn5a-coded Na channels were recently reported to play a role in sinus node pacemaking in mice (24). Meanwhile, the latter scenario may be likely; a functional defect of the Na channel can result in a reduction of impulse propagation in the vicinity of the sinus node. Indeed, Scn5a-coded Na channels were distributed in the periphery of the mouse sinus node (24), and heterozygous Scn5a knockout mice showed a prolongation of the P wave as well as the PR interval, suggesting slow conduction within the atria and atrioventricular conduction system (25). Furthermore, a failure in impulse conduction in the adjacent atrial myocardium (exit block) is one of the pathophysiological bases of human SSS (26,27).
Benson et al. (10) recently reported a young man with congenital SSS who had compound heterozygous SCN5A mutations, T220I and R1623X. Three members of his family had R1623X alone, and showed only subclinical ECG abnormality (first-degree AVB). On the other hand, our R1623X case (K-185), despite the absence of additional mutations, demonstrated more prominent phenotypes; not only SSS but also typical symptomatic Brugada syndrome with spontaneous VF episode. These apparent discrepancies in clinical features may suggest the presence of environmental or other genetic factors modifying the phenotypes.
Notably, we found a frame-shift SCN5A mutation (K1578fs/52) in a familial SSS case (K-202). Four family members, including the proband, had received a pacemaker after being diagnosed with SSS. To assess the association with Na channel dysfunction in this SSS case, we carried out a pilsicainide provocation test. A low dose of intravenous pilsicainide induced a Brugada-type elevation in ST and programmed electrical stimulation-provoked VT. This case provides an important insight into the potential overlap between SSS and Brugada syndrome. In familial SCN5A-linked SSS cases, the presence of asymptomatic Brugada syndrome may have to be taken into consideration.
In summary, our studies showed Brugada plus bradyarrhythmias (SSS/AVB) type of overlap syndrome was caused by single SCN5A mutations that result in a complete loss-of-function in cardiac Na channels. In order to reveal the cellular and molecular mechanisms by which SCN5A mutations produce a variety of phenotypes, further studies will be needed, including the establishment of animal models of cardiac Na channelopathies.
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Acknowledgments
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The authors thank Dr. Alfred L. George, Jr. (Vanderbilt University, Nashville, Tennessee), for providing them with hH1 cDNA.
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Footnotes
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This work is supported by research grants from the Ministry of Education, Science, Sports and Culture of Japan (#16209025) and the Ministry of Health, Labour, and Welfare for Clinical Research for Evidence-Based Medicine (#1508041).
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