Author + information
- Received January 22, 2014
- Revision received March 23, 2014
- Accepted April 23, 2014
- Published online July 8, 2014.
- Dan Hu, MD, PhD∗∗ (, )
- Hector Barajas-Martínez, PhD∗,
- Ryan Pfeiffer, BSc∗,
- Fabio Dezi, MS∗,
- Jenna Pfeiffer, AS∗,
- Tapan Buch, MS∗,
- Matthew J. Betzenhauser, PhD∗,
- Luiz Belardinelli, PhD†,
- Kristopher M. Kahlig, PhD†,
- Sridharan Rajamani, PhD†,
- Harry J. DeAntonio, DO‡,
- Robert J. Myerburg, MD§,
- Hiroyuki Ito, MD‖,
- Pramod Deshmukh, MD¶,
- Mark Marieb, MD#,
- Gi-Byoung Nam, MD, PhD∗∗,
- Atul Bhatia, MD††,
- Can Hasdemir, MD‡‡,
- Michel Haïssaguerre, MD§§,
- Christian Veltmann, MD‖‖,
- Rainer Schimpf, MD¶¶,
- Martin Borggrefe, MD¶¶,
- Sami Viskin, MD## and
- Charles Antzelevitch, PhD∗∗ ()
- ∗Masonic Medical Research Laboratory, Utica, New York
- †Gilead Sciences, Fremont, California
- ‡East Carolina Heart Institute, Brody School of Medicine, East Carolina University, Greenville, North Carolina
- §University of Miami Miller School of Medicine, Miami, Florida
- ‖Department of Cardiology, Showa University, Tokyo, Japan
- ¶Guthrie Clinic, Sayre, Pennsylvania
- #Yale University School of Medicine, New Haven, Connecticut
- ∗∗Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Republic of South Korea
- ††Aurora Cardiovascular Services, Milwaukee, Wisconsin
- ‡‡Department of Cardiology, Ege University School of Medicine, Izmir, Turkey
- §§Hôspital Cardiologique du Haut Lévêque, Université Bordeaux II, Pessac, France
- ‖‖Department of Cardiology and Angiology, Hannover Medical School, Hannover, Germany
- ¶¶University Medical Centre Mannheim, German Centre for Cardiovascular Research, Heidelberg/Mannheim, Mannheim, Germany
- ##Department of Cardiology, Tel Aviv Sourasky Medical Center, Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel
- ↵∗Reprint requests and correspondence:
Dr. Charles Antzelevitch or Dr. Dan Hu, Masonic Medical Research Laboratory, 2150 Bleecker Street, Utica, New York 13501-1787.
Background BrS is an inherited sudden cardiac death syndrome. Less than 35% of BrS probands have genetically identified pathogenic variants. Recent evidence has implicated SCN10A, a neuronal sodium channel gene encoding Nav1.8, in the electrical function of the heart.
Objectives The purpose of this study was to test the hypothesis that SCN10A variants contribute to the development of Brugada syndrome (BrS).
Methods Clinical analysis and direct sequencing of BrS susceptibility genes were performed for 150 probands and family members as well as >200 healthy controls. Expression and coimmunoprecipitation studies were performed to functionally characterize the putative pathogenic mutations.
Results We identified 17 SCN10A mutations in 25 probands (20 male and 5 female); 23 of the 25 probands (92.0%) displayed overlapping phenotypes. SCN10A mutations were found in 16.7% of BrS probands, approaching our yield for SCN5A mutations (20.1%). Patients with BrS who had SCN10A mutations were more symptomatic and displayed significantly longer PR and QRS intervals compared with SCN10A-negative BrS probands. The majority of mutations localized to the transmembrane-spanning regions. Heterologous coexpression of wild-type (WT) SCN10A with WT-SCN5A in HEK cells caused a near doubling of sodium channel current compared with WT-SCN5A alone. In contrast, coexpression of SCN10A mutants (R14L and R1268Q) with WT-SCN5A caused a 79.4% and 84.4% reduction in sodium channel current, respectively. The coimmunoprecipitation studies provided evidence for the coassociation of Nav1.8 and Nav1.5 in the plasma membrane.
Conclusions Our study identified SCN10A as a major susceptibility gene for BrS, thus greatly enhancing our ability to genotype and risk stratify probands and family members.
- Brugada syndrome
- cardiac arrhythmias
- cardiac conduction disease
- sudden cardiac death
Brugada syndrome (BrS), which was introduced as a new clinical entity in 1992 (1), is an inherited sudden cardiac death (SCD) syndrome characterized by the appearance of prominent J waves or ST-segment elevation in leads V1 to V3 on an electrocardiogram (ECG). An outward shift in the balance of ion channel currents flowing during the early phases of the cardiac action potential have been shown to create the substrate for the development of life-threatening arrhythmias in BrS (2). The syndrome has been associated with 13 genotypes (BrS1 to BrS13) displaying autosomal dominant inheritance (3,4). To date, more than 300 BrS-related mutations in SCN5A have been described (5), accounting for the vast majority (>75%) of BrS genotype-positive cases but only 11% to 28% of total BrS probands. Approximately 65% of BrS probands remain genetically undetermined. Thus, there is a pressing need to identify new BrS susceptibility genes for the purpose of early diagnosis, risk stratification, and targeted treatment (6,7). A similar situation is encountered in other inherited cardiac arrhythmia syndromes, including early repolarization syndrome (ERS), cardiac conduction disease (CCD), bradycardia, idiopathic ventricular fibrillation (VF), atrial fibrillation (AF), and right bundle branch block (RBBB).
Nav1.8 (encoded by SCN10A), like Nav1.5 (encoded by SCN5A), is a tetrodotoxin-resistant voltage-gated sodium channel located adjacent to SCN5A on human chromosome 3p21–22 (8,9). Until recently, Nav1.8 was principally considered a neuronal sodium channel involved in nociception. The amino acid sequences of human Nav1.8 and Nav1.5 are similar (70.4%). Recent evidence has implicated SCN10A in the electrical function of the heart (10–12). Several genome-wide association studies have reported that single nucleotide polymorphisms in SCN10A are associated with CCD and arrhythmogenesis (13–21). The present study examined the hypothesis that variations in SCN10A contribute to BrS by modulating the expression of the Nav1.5 current, the principal cardiac sodium channel. Preliminary results have been reported in abstract form (22).
Detailed methods are provided in the Online Appendix.
Clinical analysis and participants
The clinical diagnosis of BrS was on the basis of criteria provided in the 2005 Consensus Conference document (23), and the clinical diagnosis of ERS was on the basis of criteria suggested in our recent review of the J-wave syndromes (24). Informed consent was obtained from all patients upon referral to the Masonic Medical Research Laboratory for genetic testing, and patients were tracked anonymously. This study was approved by the regional institutional ethics review board and conducted according to Declaration of Helsinki principles. For each patient, we collected information on age at time of diagnosis, sex, clinical presentation, family history, and therapy.
Genetic screening and analysis
Genomic DNA was extracted from peripheral blood leukocytes and amplified. All known BrS genes and SCN10A were amplified and analyzed by direct sequencing as previously described (25). The primer sequences for SCN10A are shown in Online Table 1 (reference sequence: NM_006514). More than 200 ethnically matched, healthy controls, plus all available online databases for allele frequency, conservation score, and in silico pathogenic prediction tools, were probed for prediction of pathogenicity of the variants found.
Coexpression of NaV1.5 and NaV1.8 for coimmunoprecipitation analysis and electrophysiological investigations
Site-directed mutagenesis was performed on full-length human wild-type (WT) and mutant SCN10A-3XFLAG complementary DNA cloned in pCMV2 vector, the WT SCN3B cloned in pCMV6-XL6 vector, and the WT SCN5A cloned in pcDNA3.1. Coimmunoprecipitation (Co-IP) studies were performed using HEK293 cells transfected with SCN5A, and SCN10A and SCN3B plasmids were also used for studies. Total protein was isolated 24 h after transfection with lysis buffer supplemented with protease inhibitors for Co-IP experiments. Membrane currents were measured with whole-cell patch-clamp techniques using TSA201 cells as previously described (25).
Data are presented as mean ± SD unless otherwise noted. For statistical analysis, 2-tailed Student t test and analysis of variance coupled with Student–Newman–Keuls test were used to compare 2 groups and more than 3 groups of continuous variables separately. Chi-square test was used for comparison of categorical variables (SigmaStat; Systat Scientific Inc., San Jose, California). Differences were considered statistically significant at a value of p < 0.05.
We systematically evaluated 150 unrelated patients with BrS and 17 family members using genetic screening (Table 1). Most patients were male (n = 101; 67.3%), with a mean age at diagnosis of 44.5 ± 16.1 years. A total of 116 patients (77.3%) were symptomatic, including 39 (26.0%) with syncope and 20 (13.3%) who experienced cardiac events, documented as aborted cardiac arrest or SCD. Twenty-nine (19.3%) had a family history of cardiac events or SCD. A type 1 Brugada ECG pattern, characterized by a prominent J-wave appearing as a coved type ST-segment elevation, was observed spontaneously in 57 patients (38.0%) (Fig. 1A), appeared after treatment with sodium channel blockers in 76 patients (50.7%) (Fig. 1B) or during fever in the remaining 17 patients (11.3%) (Fig. 1C). Some patients with BrS also displayed ERS (Fig. 1D), CCD (Fig. 1E), RBBB (Fig. 1F), ventricular tachycardia (VT)/VF, or AF.
Mutation yield and analysis
Overall, 17 putative pathogenic SCN10A rare variants (16 missense and 1 frameshift mutation) were identified in 25 probands (Fig. 2A, Tables 2 and 3⇓⇓). Seven family members were positive for SCN10A variants. Eleven mutations were identified only once (64.7%), whereas 6 variants were found in multiple unrelated patients (Fig. 2B). The most frequent mutation was R14L (Fig. 1A), which was carried by 4 BrS probands. The other mutations/rare polymorphisms present in the population were V1697I (n = 3), G1662S (n = 3), I206M (n = 2), I1225T (n = 2), and R1869C (n = 2). Most variants localized to the transmembrane-spanning regions (P-loop in 42.3% and S1 to S4 in 23.1% of BrS probands) (Fig. 2C).
Among the 25 SCN10A mutations or rare variant carriers, 6 carried a secondary mutation in 1 of the 12 known BrS susceptibility genes (24.0%) (Table 2). F938YFSX12, G1406D, and N1715T are novel variants in SCN10A that were not previously reported (Table 3). A majority of missense mutations (13 of 16) were in highly conserved residues and showed minor allele frequencies (MAF) of 0 to 0.002 in control databases. None were found in more than 400 reference alleles in our healthy controls. All but 1 (T137M) of these 13 mutations were predicted to be damaging by in silico prediction tools (Table 3). The MAF of S1337T was 0.0047, that of V1697I was 0.0044, and that of I206M was 0.0046 in our controls. All 4 cases carrying these 3 rare polymorphisms were middle-aged men (31 to 58 years of age), and 3 were symptomatic.
Overlapping phenotypes of probands with SCN10A variants
With a positive proband yield of 16.7%, the prevalence of SCN10A in BrS probands approached our historical yield for SCN5A mutations, which was 20.1% (Fig. 2D). Of the 25 cases of SCN10A+ BrS, 23 (92.0%) displayed overlapping phenotypes (Table 2). In cases of BrS with overlapping phenotypes (such as CCD and early repolarization patterns in leads other than V1 to V3), the SCN10A+ positive proband yield was greater (Table 1). Patients with BrS who had SCN10A mutations were more symptomatic (syncope, SCD, chest pain) and displayed longer PR and QRS intervals (193.4 ± 31.8 ms and 105.7 ± 18.9 ms) compared with SCN10A− BrS probands (171.5 ± 38.4 ms and 97.3 ± 17.3 ms; p < 0.05). No differences in heart rate, QT interval, or Bazett QTc interval were observed. The yield of SCN10A+ BrS probands was greater in male (19.8%) than in female (10.2%) subjects in general (Fig. 2F). This difference was not observed in the subgroup of patients with BrS who had CCD but was more obvious in the patients with BrS without CCD. Figure 2E shows yield as a function of age. The yield of probands with a spontaneous type 1 Brugada ECG pattern was 15.8%, which was similar to that in cases of BrS unmasked with a sodium channel blocker (14.5%). Interestingly, BrS probands diagnosed during fever showed a much higher yield (5 of 17; 29.4%) for SCN10A variants; all were male.
The average PR interval (PRI) for BrS probands with CCD was 218.3 ± 34.59 ms (maximum PRI: 328 ms). The yield of SCN10A+ in this cohort was significantly higher (33.3%) than in those without CCD (11.4%) (p < 0.01). Compared with SCN10A− subjects, those with SCN10A+ CCD and BrS had a higher incidence of VT/VF, SCD, and chest pain (Table 1).
A total of 24 patients with BrS displayed an early repolarization pattern in leads other than V1 to V3. Seven of these probands and 2 family members were positive for SCN10A mutations, including 5 probands with global J-point/wave elevation (ERS3: 71.4%), indicating a higher correlation of SCN10A with BrS and ERS compared with BrS phenotype alone. In the case pictured in Figure 1D, the proband presented with global J-point elevation (ERS/BrS), bradycardia, and a family history of SCD. He and his affected family members carried the same SCN10A-G1662S mutation (details are provided in the Online Appendix).
SCN10A mutations were identified in 12 of the 33 patients with BrS presenting with VT/VF. BrS appeared spontaneously in 5 cases (41.7%), 2 cases were unmasked during fever (16.7%), and the rest were unmasked with use of sodium channel blockers (41.7%). Including those with pediatric bradycardia, the average heart rate of the 24 probands with bradycardia and BrS was 51.4 ± 1.7 beats/min. SCN10A mutations were identified in 5 cases. Four family members in 3 families also were positive for SCN10A mutations (G1662S for 2, R14L for 1, and F938Y FSX12 for 1), indicating clear genetic penetrance. SCN10A-S1337T and R1869C were found in 2 AF probands with BrS phenotypes. The SCN10A-N1715 mutant carrier presented with BrS and an RBBB ECG pattern, an overlapping phenotype recently highlighted by Aizawa et al. (26) (Fig. 1F).
Functional expression studies
For functional characterization, SCN5A/WT, SCN10A/WT, or SCN5A/WT + SCN10A/WT was coexpressed with SCN3B/WT in HEK293 cells (Fig. 3A). Peak sodium channel current (INa) amplitude at −35 mV was −462.8 ± 83.2 pA/pF for SCN5A/WT + SCN3B/WT. Addition of SCN10A/WT yielded a near doubling of peak INa to −859.7 ± 98.9 pA/pF (p < 0.01). In contrast, coexpression of SCN10A/WT + SCN3B/WT alone generated very low amplitude current (−12.2 ± 3.3 pA/pF; p < 0.01 compared with the other 2 groups) (Fig. 3B). Coexpression of the SCN10A mutants, R14L and R1268Q, with SCN5A/WT and SCN3B/WT caused a major loss of function of INa (Figs. 3C to 3I). SCN10A-R14L reduced peak INa density to −177.5 ± 49.5 pA/pF (p < 0.01 vs. SCN10A-WT) and caused a significant positive shift of half-activation voltage (p < 0.05). SCN10A-R1268Q reduced the current density to −133.9 ± 36.6 pA/pF (p < 0.01 vs. SCN10A/WT) with no change in activation parameters. The half-inactivation voltage of SCN10A-R1268Q was 7.7 mV more negative than that of SCN10A-WT when coexpressed with SCN5A-WT + SCN3B-WT (p < 0.05). Recovery from inactivation was similar in the 2 mutant groups, but both were slower than WT channels (p < 0.05 in both τf and τs, respectively). The gating defects caused by SCN10A-R14L and SCN10A-R1268Q served to reduce sodium channel availability (Online Table 2).
We examined the capability of Nav1.5 to physically interact with Nav1.8 using Co-IP. The channels were expressed in HEK293 cells either alone or in combination and isolated by pull-down using an antibody to the FLAG on SCN10A. Figure 4A shows the protein input for each condition, demonstrating the presence of the transfected proteins under the appropriate conditions. Figure 4B shows the association between Nav1.5 and Nav1.8 when coexpressed (lane 5, bottom panel). This interaction was lost when the pull-down antibody was omitted (lane 4, bottom panel) and did not occur due to in vitro mixing of the protein lysates (lane 6, bottom panel).
SCN10A in the heart and its role in arrhythmogenesis
SCN5A and SCN10A are located in close proximity to each other in chromosome 3p22. In 1997, SCN10A protein (also referred to as PN3, SNS, and hereafter Nav1.8) was initially shown to be specifically expressed in rat and human dorsal root ganglia (27). Real-time polymerase chain reaction and immunostaining methodologies have detected a low level of expression of the SCN10A gene product in mouse and human heart tissues, with somewhat higher levels in the Purkinje system (12,15,18). Nav1.8 immunoreactivity was detected in intracardiac neurons and ganglia in human myocardium (28). With the in situ hybridization method, SCN10A displayed a similar distribution pattern of Scn5a in mouse hearts (10). These findings notwithstanding, some researchers deny the existence of Nav1.8 in cardiac myocytes. For example, Verkerk et al. (11) reported that SCN10A expression modulates cardiac electrical activity primarily by regulating the firing patterns of intracardiac neurons. Conflicting data also resulted from other in vivo and in vitro experimental studies in the animal models (12,15).
The localization, expression level, and functional role of Nav1.8 in the heart remain highly controversial. Nonetheless, our results support the conclusion that SCN10A variants play a key role in developing arrhythmogenic J-wave syndromes, including both BrS and ERS, likely through a direct effect on Nav1.5-mediated cardiac INa (Central Illustration). A key role for Nav1.8 in human cardiac electrophysiology is supported by genome-wide association studies, showing that SCN10A plays an important role in cardiac conduction disease by influencing the duration of the PRI and QRS interval as well as heart rate and arrhythmic risk. Several independent loci within SCN10A have been identified, including rs6795970 (13–18), rs6798015 (16,19), rs6800541 (16,20), rs7430477 (16), and rs12632942 (15). A recent genome-wide association study of 312 subjects with BrS and 1,115 controls reported a significant association signal at the SCN10A locus (rs10428132), providing additional support for a role for SCN10A variants, in this case 3′–untranslated region or intronic, in the development of BrS (21).
Clinical and genetic findings related to SCN10A
We identified 17 putative pathogenic SCN10A variants in 25 of the 150 BrS probands screened. A positive proband yield of 16.7% approached our historical yield of 20.1% for SCN5A and a yield of 11% to 28% (21% average) reported in the international compendium of SCN5A mutations (5). In our study, as in the international compendium study, there was a male predominance of the BrS phenotype (67% vs.78%). The latter has a similar yield between male and female subjects (20% vs. 22%, respectively).This was not the case in our screen for SCN10A mutations, where the yield was greater for male subjects (20% vs. 10%).
In our study, 66.7% of SCN10A mutations were localized to transmembrane and pore-forming domains; this is in comparison to the nearly 75% reported in the SCN5A compendium. Of all BrS-related SCN10A variants, one was a frameshift and the rest were missense mutations (94.1%), whereas in the compendium of SCN5A mutations, two-thirds were reported to be missense mutations.
Six of the 25 cases reported were also found to carry a second potentially pathogenic BrS mutation (Table 2). As such, the number of SCN10A variants that we counted as potentially responsible for the clinical phenotype could be an overestimate. This notwithstanding, the 3 mutations in calcium channel genes were found in patients with a prolonged PRI (>180 ms) and normal QTc interval, pointing to a clear predominance of the SCN10A mutation leading to a loss of function of INa. The KCNJ8 mutation likewise was accompanied by a prolonged PRI. The 2 SCN5A mutations were both accompanied by very prolonged PRI (240 to 280 ms), suggesting that both the SCN5A and SCN10A variants contributed to the clinical phenotype. Interestingly, the yield of BrS probands unmasked by fever was much higher in the case of SCN10A versus SCN5A mutations (29.4% vs. 17.2%) (Dan Hu et al., unpublished data, February 2014). There was a higher association with SCD and syncope in the case of SCN10A versus SCN5A mutations. Also interesting is the larger number of complaints of chest pain in the SCN10A+ group than in the SCN10A− group, which was not observed when SCN5A+ and SCN5A− cases were compared.
More than 90% of the subjects with SCN10A+ BrS presented with mixed phenotypes, the most common of which was CCD. It is not surprising that, as with SCN5A mutations (39% when the PRI was >200 ms vs. 8% when the PRI was <200 ms) (6), the yield of SCN10A mutants was much higher in BrS probands with a prolonged PRI (31% in those with a PRI >200 ms vs.11% in those with a PRI <200 ms).
We observed a high prevalence of SCN10A variants associated with BrS and ERS, most of which: 1) are in amino acid residues that are highly conserved in mammalian species; 2) exhibit a very low MAF in controls; 3) are predicted by in silico models to be pathogenic; 4) show good genotype-phenotype correlation in cases in which family pedigrees are available; and 5) show a major loss of function in INa in the 2 cases in which the variants were functionally coexpressed with SCN5A, suggesting that SCN10A is an important susceptibility gene for BrS and for other cardiac syndromes, including CCD, ERS, AF, VT/VF, RBBB, and bradycardia. SCN10A is known to be involved in nociception (29). Our referring physicians did not report altered nociception other than an increased incidence of chest pain.
Mechanisms underlying SCN10A modulation of electrical function of the heart
Alpha-subunit interactions have previously been shown to aggravate as well as ameliorate disease phenotypes. The combination of SCN2A and KCNQ2 mutations causes severe seizure manifestations (30), an Scn8a mutation has been shown to compensate for haploinsufficiency of Scn1a (31), and SCN9A mutations are known to modify the severity of SCN1A-related Dravet syndrome (32). A recent study of BrS reported a dominant-negative effect of SCN5A mutant channels interacting with SCN5A-WT channels (33). Given their proximity to one another, SCN5A and SCN10A may be subject to common regulatory mechanisms, such as transcriptional control by TBX3 and TBX5 (10).
We hypothesize that SCN10A modulates the activity of the canonical cardiac sodium channel encoded by SCN5A in the heart. Our coexpression studies provide evidence in support of this hypothesis, showing that Nav1.5 and Nav1.8 coassociate when expressed together. The observed functional interaction between Nav1.5 and Nav1.8 may suggest either a direct physical interaction between the 2 channels or an indirect interaction within a larger protein complex. SCN10A-WT causes a gain of function of Nav1.5 current, whereas SCN10A mutants (R14L and R1268Q) cause a loss of function of Nav1.5 current, which is expected to reduce excitability and lead to development of the arrhythmogenic substrate responsible for BrS and ERS as well as CCD, VT/VF, AF, RBBB, and bradycardia.
Of the 16 missense mutations uncovered in this study, only 2 were functionally characterized. Despite these limitations, 13 of these variants were totally absent from our own ethnically matched controls and are either absent or negligibly present in all available public databases. Moreover, these mutations are located in highly conserved residues and are predicted to be pathogenic by in silico prediction tools.
Our Co-IP analysis pointing to a coassociation of Nav1.5 and Nav1.8 proteins was performed after coexpression of SCN5A and SCN10A in HEK cells. Ideally, these studies should be performed in native human ventricular myocytes. This, however, must await the availability of more reliable Nav1.8-specific antibodies. Additional studies are needed to expand the size of the cohort and to conduct functional expression of WT and mutant SCN10A in native myocytes or alternatively in induced pluripotent stem cell–derived cardiomyocytes.
The findings of this study extend our knowledge of the role of Nav1.8 in the heart and provide an explanation for why SCN10A variants cause conduction and rhythm disturbances, some of which were previously identified by genome-wide association studies. Our data identify SCN10A as a new BrS susceptibility gene and a potential target for genetic screening and antiarrhythmic intervention. We showed colocalization and coassociation of Nav1.8 and Nav1.5 in the plasma membrane and a gain of function of SCN10A-WT and loss of function of SCN10A mutants on Nav1.5 INa. Male patients with BrS who are 11 to 50 years of age and present with a prolonged PRI and QRS interval, VT/VF, ERS, and/or symptoms (syncope, SCD, chest pain) have the highest probability of carrying an SCN10A variant. The spectrum of SCN10A arrhythmic phenotypes, including BrS, ERS, CCD, VT/VF, AF, RBBB, and bradycardia, is similar to that of SCN5A variants. With a yield of 16.7% for SCN10A, a genotype can now be identified in more than 50% of BrS probands.
COMPETENCY IN MEDICAL KNOWLEDGE: BrS and ERS are responsible for ventricular fibrillation and sudden cardiac death of young adults. Fewer than 35% of BrS probands have genetically identified pathogenic variants. The identification of SCN10A as a major susceptibility gene for BrS and ERS greatly enhances the ability to risk stratify probands and family members by genotyping.
TRANSLATIONAL OUTLOOK 1: The ability of mutant neuronal sodium channels to cause a loss of cardiac sodium channel activity provides insights into mechanisms by which SCN10A variants may contribute to overlap syndromes such as BrS, ERS, cardiac conduction disease, and various bradycardia phenotypes.
TRANSLATIONAL OUTLOOK 2: These findings help to delineate the role of neuronal sodium channels in the electrical function of the heart.
The authors thank Drs. Philip J. Iuliano and Ramon Saldana for clinical assistance, Judy Hefferon and Robert J. Goodrow Jr. for technical assistance, and Susan Bartkowiak for maintaining the Masonic Medical Research Laboratory genetic database.
This study was supported by the Masons of New York, Florida, Massachusetts, Connecticut, Maryland, Wisconsin, and Rhode Island. Drs. Hu and Barajas-Martínez were supported by Consejo Nacional de Ciencia y Tecnología (CONACYT; FM201866). Dr. Betzenhauser was supported by a National Research Service Award fellowship (F32-HL107029). Drs. Belardinelli, Kahlig, and Rajamani are employees of Gilead Sciences. Dr. DeAntonio is a speaker for Boehringer Ingelheim. Dr. Antzelevitch was supported by grants from the National Heart, Lung, and Blood Institute/National Institutes of Health (HL47678) and the New York Stem Cell Foundation (C026424); and is a paid consultant for Gilead Sciences. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- atrial fibrillation
- Brugada syndrome
- cardiac conduction defect
- early repolarization syndrome
- sodium channel current
- minor allele frequency
- PR interval
- right bundle branch block
- sudden cardiac death
- ventricular fibrillation
- ventricular tachycardia
- Received January 22, 2014.
- Revision received March 23, 2014.
- Accepted April 23, 2014.
- American College of Cardiology Foundation
- Brugada P.,
- Brugada J.
- Crotti L.,
- Marcou C.A.,
- Tester D.J.,
- et al.
- Ackerman M.J.,
- Priori S.G.,
- Willems S.,
- et al.
- Sangameswaran L.,
- Delgado S.G.,
- Fish L.M.,
- et al.
- Verkerk A.O.,
- Remme C.A.,
- Schumacher C.A.,
- et al.
- Yang T.,
- Atack T.C.,
- Stroud D.M.,
- et al.
- Jeff J.M.,
- Ritchie M.D.,
- Denny J.C.,
- et al.
- Ritchie M.D.,
- Denny J.C.,
- Zuvich R.L.,
- et al.
- Denny J.C.,
- Ritchie M.D.,
- Crawford D.C.,
- et al.
- Hu D.,
- Barajas-Martinez H.,
- Kahlig K.,
- et al.
- Hu D.,
- Barajas-Martinez H.,
- Burashnikov E.,
- et al.
- Aizawa Y.,
- Takatsuki S.,
- Sano M.,
- et al.
- Kearney J.A.,
- Yang Y.,
- Beyer B.,
- et al.
- Martin M.S.,
- Tang B.,
- Papale L.A.,
- et al.
- Clatot J.,
- Ziyadeh-Isleem A.,
- Maugenre S.,
- et al.