© 1999 American Heart Association, Inc.
Clinical Research |
A Single Na+ Channel Mutation Causing Both Long-QT and Brugada Syndromes
From the Departments of Clinical Genetics (C.B., A.V.P., I.M.v.L, M.M.A.M.M.) and Experimental and Molecular Cardiology (C.B., A.V.P., M.W.V., A.A.M.W.), Academic Medical Center, Amsterdam; Departments of Cardiology (M.P.v.d.B, J.-W.V.), Medical Genetics (G.T.-S., A.H.v.d.H.), and Paediatrics (M.Th.E.B.-B.), Groningen University Hospital, Groningen; Departments of Medical Physiology (M.B.R.) and Cardiology (A.A.M.W.), Utrecht University Hospital, Utrecht, the Netherlands; and the Interuniversity Cardiology Institute of the Netherlands (A.A.M.W.).
Correspondence to Dr A.A.M. Wilde, Department of Clinical and Experimental Cardiology, AMC, PO Box 22700, 1100 DE Amsterdam, the Netherlands. E-mail a.a.wilde{at}amc.uva.nl
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Abstract |
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Abstract—Mutations in SCN5A, the gene encoding the cardiac Na+ channel, have been identified in 2 distinct diseases associated with sudden death: one form of the long-QT syndrome (LQT3) and the Brugada syndrome. We have screened SCN5A in a large 8-generation kindred characterized by a high incidence of nocturnal sudden death, and QT-interval prolongation and the "Brugada ECG" occurring in the same subjects. An insertion of 3 nucleotides (TGA) at position 5537, predicted to cause an insertion of aspartic acid (1795insD) in the C-terminal domain of the protein, was linked to the phenotype and was identified in all electrocardiographically affected family members. ECGs were obtained from 79 adults with a defined genetic status (carriers, n=43; noncarriers, n=36). In affected individuals, PR and QRS durations and QT intervals are prolonged (P<0.0001 for all parameters). ST segment elevation in the right precordial leads is present as well (P<0.0001). Twenty-five family members died suddenly, 16 of them during the night. Expression of wild-type and mutant Na+ channels in Xenopus oocytes revealed that the 1795insD mutation gives rise to a 7.3-mV negative shift of the steady-state inactivation curve and an 8.1-mV positive shift of the steady-state activation curve. The functional consequence of both shifts is likely to be a reduced Na+ current during the upstroke of the action potential. LQT3 and Brugada syndrome are allelic disorders but may also share a common genotype.
Key Words: long-QT syndrome • Brugada syndrome • SCN5A • arrhythmia • Na+ channel
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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SCN5A, the gene that encodes the human cardiac Na+ channel
subunit,1 is mutated
in one form of the long-QT syndrome (LQT3) and in
Brugada syndrome.2 3 There are characteristic and readily
distinguishable ECG patterns in these 2 syndromes. In
LQT3 patients, a long isoelectric ST segment
precedes a peaked T wave.4 Brugada syndrome is diagnosed
on the basis of characteristic ECG features in the absence of
structural heart disease; these features include right precordial
ST-segment elevation, which may be intermittent, and which is
exacerbated by Na+ channel block and ameliorated
by isoproterenol.5 6 QT intervals have been reported to be
normal in patients with Brugada syndrome.5 Clinically,
there appears to be some overlap between the 2 syndromes, as both
exhibit a relatively high incidence of nocturnal sudden cardiac death
without prior symptoms.6 7 8
The prolonged QT interval in LQT3 results from
persistent inward Na+ current during the plateau
phase of the action potential, secondary to incomplete inactivation of
mutated channels.9 Changes in the and
ß1 subunit interaction have also been
implicated.10 Although functional abnormalities have been
described for Brugada syndrome–related SCN5A mutant
channels,3 11 the mechanism(s) whereby these explain
the Brugada phenotype are less clear.
In this study we present clinical and genetic data of a single large SCN5A-linked family, phenotypically characterized by nocturnal death and electrocardiographically by both LQT3 and Brugada syndrome features in the same patients. We show that LQT3 and the Brugada syndrome are more closely related than heretofore appreciated and can even be caused by the same mutation. We also report on the functional consequences of the Na+ channel mutation involved, as revealed by measuring Na+ channel activity in the Xenopus oocyte expression system.
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Materials and Methods |
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Patients
The study was performed according to a protocol approved by the local ethics committees. Informed consent was obtained from all patients, who were all screened by one of us. For purposes of linkage analysis, the phenotype was assigned in a subset of the family according to the criteria described in the online Materials and Methods (see http://www.circresaha.org).
After the mutation was identified (see below), a careful history, an
ECG at rest and in the supine position, and peripheral
blood samples for genotype analysis were taken from as
many other family members as possible. Patients with specific reasons
for prolongation of the QT interval were excluded from further
(electrocardiographic) analysis. We analyzed 12-lead
ECGs (paper speed, 25 mm/s), only of patients 
16 years of age,
with particular reference to rate and to PR, QRS, and QT interval (the
longest interval in any lead was taken). QTc was calculated according
to the Bazett formula. In the final analysis, mutation carriers
either are obligate carriers (by pedigree analysis) or have a
proven genetic status (see below). Individuals within this family from
which no DNA or ECGs were available were defined as mutation carriers
when they died suddenly and unexpectedly under typical circumstances
(see below).
Signal-averaged electrocardiography (SAECG) was performed in the supine position according to the method previously described for a subset of these patients.12 We considered the SAECG abnormal according to the predefined criteria.12 In 5 individuals, an invasive electrophysiological study by standard procedures was performed.
Linkage Analysis
Genotyping of microsatellite markers around the known LQT
(SCN5A, LQT4, HERG,
KCNQ1, and KCNE1) and Brugada syndrome
(SCN5A) loci was performed by standard, semiautomated
methods. Linkage analyses were carried out using the MLINK
program from the LINKAGE 5.1 package.
Mutation Analysis of SCN5A
Mutation analysis of SCN5A was done by
single-strand conformation polymorphism (SSCP) analysis
followed by direct sequence analysis of aberrant conformers.
All 28 exons of the SCN5A gene were amplified using intronic
primers designed by Wang et al13 and analyzed
in this way. Independent of the outcome of SSCP analysis, 12
exons (2, 3, 12, 17–21, 24, 26–28) were also analyzed by
direct sequence analysis.
Functional Expression
Mutant Na+ channel cDNA was prepared by
mutagenesis on the double-stranded pSP64T-hH1(sp)
plasmid.1 14 Wild-type (WT) and mutant constructs were
linearized and cRNAs were synthesized. cRNA concentration was
determined spectrophotometrically at a 260-nm wavelength.
Electrophysiology
Stage V through VI Xenopus oocytes were isolated and
injected with 5 to 20 ng of cRNA according to standard
methods.15 Voltage-clamp experiments were performed 2
to 4 days after injection, using a Geneclamp 500 2-electrode voltage
clamp amplifier (Axon Instruments). Na+ currents
were corrected for leakage current using Geneclamp leak subtraction.
Steady-state activation and inactivation parameters were
determined using protocols similar to those published previously by
Wang et al.16 Electrophysiological
experiments were performed at room temperature (21°C).
Statistical Analysis
Differences between groups (mutation carriers and noncarriers)
were compared by the Fischer exact test or unpaired Student
t test, where appropriate. A 2-tailed probability value of
<0.05 was considered statistically significant. In
electrophysiological studies, differences
between WT Na+ current and mutant
Na+ current were compared using the unpaired
Student t test.
An expanded Materials and Methods section is available online at http://www.circresaha.org.
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Results |
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The anonymized pedigree of the family is presented in Figure 1
. Linkage analysis in
a subset of the family (11 affected and 12 unaffected) revealed linkage
to SCN5A (Table 1), whereas no
evidence of linkage was detected to the LQT4,
HERG, KCNQ1, and KCNE1 loci.
Subsequent SSCP analysis of the coding region of
SCN5A using primers flanking the exon-intron boundaries
identified an aberrant conformer in exon 28 in affected family members
(Figure 2; n=53, including children). The
aberrant conformer was not present in unaffected family members nor
in 100 alleles from unrelated control individuals. DNA sequencing
of exon 28 of affected family members revealed heterozygosity for a TGA
insertion at position 5537. This insertion results in the insertion of
aspartate after tyrosine 1795 (1795insD) within the highly negatively
charged region of the C-terminal domain of the protein. SSCP
analysis of all the other exons and direct sequence
analysis of a large part of the coding region (see Materials
and Methods) in 3 affected individuals (VI-27, VI-29, and VI-30)
revealed no further abnormalities.
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We were able to trace the history of 203 family members in 8
generations (Figure 1
). ECGs were obtained from 119 individuals,
of whom 79 adults had a defined genetic status (mutation carriers,
n=43; noncarriers, n=36). Figure 3
demonstrates an example (patient VI-27). Heart rate is relatively slow,
PR and QRS durations are slightly prolonged, and the QT interval is
markedly prolonged (Figure 3B). In the right precordial
leads, ST-segment elevation is apparent (Figure 3A). Table 2 summarizes basic demographic and
electrocardiographic data of the 79 genotyped family members.
Whereas sex and age are similar in affected and nonaffected members,
mean heart rate is slightly lower (P<0.02), and conduction
parameters (PR and QRS intervals) are slightly prolonged in
mutation carriers (for both parameters;
P<0.0001). In addition, HV interval was prolonged in 4 of
the 5 carriers in whom an invasive
electrophysiological study was performed:
58, 78, 75, and 80 ms in V-1, VI-27, VI-54, and VI-60 respectively, and
50 in VI-3. SAECG was abnormal in 23 of 29 mutation carriers tested
(79%) and abnormal in 2 of 14 noncarriers (14%; P<0.001).
Figure 4 depicts normalized QT intervals
(QTc) versus heart rate in analyzed patients. QTc was clearly
prolonged in the vast majority of mutation carriers, in particular in
those in whom heart rate is slow. PR and QRS prolongation was
concomitantly present in 14 carriers, whereas only PR or only QRS
prolongation was seen in 10 carriers (and in 6 noncarriers) and 10
carriers (and in 1 noncarrier), respectively (Figure 5A). ST-segment elevation was present
in 21 of the 43 carriers versus 3 of 36 noncarriers
(P<0.001; mean values in Table 2). Figure 5B
shows QTc intervals versus ST segment elevation in individuals. In 16
carriers, both QTc is prolonged and right precordial ST segments
are elevated. In 13 carriers, only QTc was prolonged, whereas in 5
carriers (and 3 noncarriers) only ST-segment elevation was apparent. In
all 3 carriers (VI-27, VI-29, and VI-30) who received a bolus
procainamide (250 mg IV), ST-segment elevation was increased
further (see inset, Figure 3B). There were no
echocardiographic abnormalities in 29 mutation
carriers.
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] and 36
noncarriers [
]). QT intervals are particularly
prolonged at long RR intervals. However, also at normal heart rate (RR
600 to 1000 ms), QT interval is prolonged in most carriers.
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Unexpected nocturnal sudden cardiac death was the only symptom in this
family, occurring in 16 family members since 1905 (10 female, 6 male;
see online Table, available at http://www.circresaha.org). Eight
patients died suddenly under unknown circumstances. One died in the
chair of the barber while being shaved (IV-8). Death was witnessed in 5
cases, occurring between 4:00 and 7:00 AM, and the episodes
were characterized by sudden onset of gurgling and gasping, and moaning
respiration. Patients were unconscious and could not be awakened. No
electrocardiographic recordings are available from these
episodes. Previous ECGs were available in 4, all demonstrating
bradycardia with significant QT-segment prolongation. Nine victims were
obligate carriers of the aberrant gene. Three clinically affected
individuals have been evaluated in hospital, and sudden arousal during
the early morning hours did not reveal any (additional)
electrocardiographic abnormality. The mean age (±SD) of sudden cardiac
death victims was 32.3±14.63 (n=22), with 19 individuals 
40 years
(male/female ratio, 9/10).
To establish the consequences of the 1795insD insertion on the
electrophysiological properties of the
Na+ channel, macroscopic
Na+ currents (INa)
were recorded in oocytes injected with cRNA encoding either the WT
or the 1795insD mutant Na+ channel subunit.
Figure 6A shows typical families of
Na+ current traces elicited by 5-mV depolarizing
steps between -90 and +40 mV from a holding potential of -100 mV.
There was a striking difference in peak amplitudes between the WT
Na+ current (INa,WT,
Figure 6A, left) and the 1795insD mutant
Na+ current
(INa,1795, Figure 6A, right),
despite the fact that similar amounts of cRNA were injected. The
average (±SEM) current-voltage relations in Figure 6B show that
the maximal INa amplitude was 9.9±1.7 µA
(n=14) and 2.2±0.5 (n=22) for INa, WT and
INa,1795 respectively. The averaged data
were obtained from 6 different batches of oocytes. The much larger peak
amplitude of WT Na+ currents compared with
1795insD Na+ currents was a consistent
finding. In addition, the voltage for both the threshold of activation
and the maximum peak current was shifted by +5 mV for 1795insD
channels. We also determined the steady-state voltage dependence of
activation and inactivation for INa,WT and
INa,1795, as illustrated in Figure 6C. The averaged data points of the inactivation curve were
fitted with a Boltzmann function with V1/2 of
-78.7 mV and a k of -4.5 for the WT
Na+ channel (n=21) and a
V1/2 of -86.0 mV and a k of -5.0 for
the 1795insD mutant Na+ channel (n=22). These
results indicate a negative shift of the inactivation curve of the
1795insD mutant by 7.3 mV. The averaged data points of the activation
curve were fitted with a Boltzmann function with a
V1/2 of -40.2 mV and a k of 5.3
for the WT Na+ channel (n=20) and a
V1/2 of -32.1 mV and a k of 5.7 for
the 1795insD mutant Na+ channel (n=22), resulting
in an 8.1-mV positive shift of the activation curve of the 1795insD
mutant. Both shifts will result in a reduced Na+
current during the upstroke of the action potential and a reduced
Na+ window current. Recovery from inactivation
(Figure 6D) was slightly, but significantly, slower for the
1795insD mutant channel. When the data were fitted with a single
exponential function, mean time constants (±SEM) were 12.2±0.6 ms
(n=22) and 14.7±0.7 ms (n=22) for the WT and the 1795insD mutant
Na+ channel, respectively.
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, n=14) and the 1795insD
mutant (•, n=22) Na+ channel. Data are mean±SEM. C,
Steady-state voltage dependence of activation for WT (
, n=21) and 1795insD mutant (
, n=22)
Na+ channels. See text for further discussion. D, Recovery
from inactivation of WT (
Because LQT3 has been associated with incomplete
inactivation of the Na+ channel, resulting in a
persistent Na+ current, we sought to determine
whether a reduced rate of inactivation or incomplete inactivation was
also present in our 1795insD mutant Na+
channel. INa,WT and
INa,1795 were recorded at -20 mV, and
current decay was fitted with either a single- or double-exponential
function (not shown). The results showed that both the fast and the
slow time constant of inactivation were only slightly, and not
significantly, larger for the 1795insD Na+
channel (mean±SEM, WT: 
fast=0.98±0.06,
slow=7.1±0.7 [n=20]; 1795insD:
fast=1.15±0.06,
slow=10.49±2.9 [n=22]). Also, the
study of procainamide- and tetrodotoxin-sensitive
1795insD Na+ currents did not reveal the presence
of a persistent inward current. Because 1795insD
Na+ currents were of very small amplitude, we
considered the possibility that a persistent inward current, usually
<2% of the peak current, was too small to distinguish. Unfortunately,
attempts to increase the expression level by injecting 5 to 10 times
higher amounts of cRNA increased peak 1795insD
Na+ currents no further than 3 µA.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We describe a single, large SCN5A-linked family with phenotypic characteristics of both LQT3 and Brugada syndrome in the same patients. QT-interval prolongation and abnormal T-wave configuration are seen particularly at slow heart rates, and as shown previously in individual patients in this family, normalization occurs as rate increases.12 Similar steep APD- and QT-rate relationships have been observed in LQT3 patients7 and in experimental models mimicking LQT3.17 It is likely that normal K+ currents result in physiological or supraphysiological cardiac repolarization during fast rates in these patients. In contrast, incomplete inactivation of INa (as a result of mutation in the SCN5A gene) results in abnormal repolarization at slow rates.7 9 Further compounding the QT abnormality is the bradycardia seen in affected patients (Figure 4
), as has
been reported for other LQT3
patients.10 It is likely that these bradycardia-induced
QT-interval abnormalities and resultant torsade de pointes underlie the
high incidence of nocturnal sudden death in this and other
LQT3 families.7 8 Alternatively, a
high vagal tone, likely of importance in Brugada syndrome–related
ventricular fibrillation (see below),18 may be
causally related to nocturnal death in this family.
The Brugada syndrome is characterized by right precordial
ST-segment elevation with or without apparent right
ventricular conduction delay.5 6 19 More
general, mild, intraventricular conduction defects
are usually also present, manifested by prolonged HV intervals and
abnormal QRS axes.8 The ST abnormalities can be transient
and can be modified by pharmacological interventions. Brugada syndrome
patients present with syncope or out-of-hospital cardiac arrest and
may have a family history of sudden cardiac death.
Asymptomatic individuals appear to have a poor
prognosis.5 Sudden cardiac death and documented episodes
of ventricular fibrillation without antecedent QT abnormalities
occur preferentially at night. This is especially the case in the
syndrome of sudden unexplained death in young South-Asian men, which
appears to be part of the clinical spectrum.20 Causally
related enhancement of vagal tone, just before the (fatal)
arrhythmia, has been suggested,18 and
acetylcholine augments the ST-segment changes.21 Note that
1 of our patients died suddenly while being shaved (potentially a
carotis sinus massage, which may increase vagal tone). In the family,
significant ST-segment elevation was present in 49% of patients.
Procainamide exaggerated the effects in the 3 patients in which
it was tested (Figure 3). In addition,
intraventricular conduction defects (prolonged QRS
and HV interval, late potentials) were generally present. Although
the conduction delay is mild, the concomitant presence of both PR and
QRS conduction delay in a significant subset of affected patients
(Figure 5A) suggests a hampered conduction in different cardiac
compartments. These features are all compatible with the Brugada
syndrome diagnosis. Importantly, 16 affected subjects displayed both
right precordial ST-segment elevation and QT-prolongation (Figures 3 and 5B).
In affected family members, 3 nucleotides (TGA) were
inserted at nucleotide position 5537. This mutation gives
rise to the insertion of a charged amino acid (Asp) after residue 1795
in the C-terminal end of the subunit of the
Na+ channel (1795insD). No further abnormalities
were found in SCN5A. LQT3 (by
definition) and Brugada syndrome are allelic disorders with involvement
of SCN5A.2 3 Mutations in the
C-terminal end have been linked to both syndromes in individual
families or patients.10 11 The typical ECG features
associated with the Brugada syndrome, as well as the
ventricular and atrial conduction delays in
1795insD-affected patients, suggest a reduction in
INa amplitude. It can be postulated that
the balance between inward and outward currents during the
characteristic phase 1 of the epicardial action potential may be
shifted toward (enhanced) repolarization by the reduction in
INa amplitude. Loss of the epicardial
action potential plateau phase may ensue and cause transmural
heterogeneity and ST elevation as a result of
transmural current flow from endocardium to
epicardium.6 22 The functional consequences of
1795insD may particularly affect the contribution of the right
ventricle, where epicardial action potentials are proportionately well
represented and exhibit a particularly well established
"spike and dome morphology."23 Indeed, in our and
other patients with the Brugada syndrome,6 21 reduction of
INa by Na+ channel
blockers augments the ST-segment abnormalities (Figure 3). The
results from our expression study are in line with a reduced
Na+ current. We found a 7.3-mV negative shift of
the steady-state inactivation curve and an 8.1-mV positive shift of the
steady-state activation curve of the 1795insD mutant channels. The
functional consequence of both shifts is likely to be a reduced
Na+ current during the upstroke and phase 1 of
the action potential. Moreover, 1795insD Na+
currents had 5-fold smaller amplitudes than WT currents, which is less
than expected on ground of the shifts in activation- and inactivation
curves alone. It suggests the presence of additional differences, such
as a reduced Na+ channel density or conductance.
Our findings are different from functional characterization of the
Brugada syndrome SCN5A mutations described so far. These
included faster recovery from inactivation and a negative shift of the
steady-state activation curve.3 11
It is difficult to link the prolonged QT interval in these patients to the observed kinetic characteristics of the 1795insD mutant channel. In general, prolongation of the repolarization process suggests an increase in net inward current during the plateau phase of the action potential. Indeed, it has been shown that persistent inward Na+ current, secondary to incomplete inactivation, underlies LQT3.9 Analysis of procainamide- and tetrodotoxin-sensitive currents did not reveal such a persistent Na+ current in our study. The observed small increase in inactivation time constants is probably not sufficient to account for the prolonged QT interval, certainly not in view of the overall reduction in INa amplitude.
To ultimately decide on the presence (or absence) of a persistent
inward current, further experiments are needed. Several factors may
have hampered its detection in the present study. First,
experiments were performed at room temperature. It has been shown that
the kinetics of both WT and 
KPQ Na+ channels
are highly sensitive to temperature, having 2-fold faster activation
and inactivation kinetics at 33°C compared with 23°C and a positive
shift of the activation and steady-state inactivation at the higher
temperature.24 Second, ion channel properties may be
dependent on the expression system.25 In the present
study Na+ channels were expressed in a
nonmammalian system. Third, it has been shown that the nearby D1790G
and E1784K mutations affect the voltage dependence of
INa inactivation by altered interaction
between the and ß1
subunit.10 26 Interaction of the
ß1 subunit with the subunit also
significantly affects INa
amplitude.27 Hence, it is conceivable that
coexpression of the ß1 subunit with the
1795insD mutant subunit uncovers kinetic properties of the channel
that may give rise to prolongation of the repolarization process. In
this respect it should be noted, however, that coexpression of the
subunit with the ß1 subunit did not affect the
persistent inward current in case of the E1784K mutant.26
Finally, single-channel measurements in multichannel patches may be
used to reveal late openings indicative for the presence of a
persistent current.
In summary, we describe a large SCN5A-linked family, characterized by QT prolongation, in particular during bradycardia; discrete conduction disturbances throughout the heart; and nocturnal sudden cardiac death. Electrocardiographic features of LQT3 and Brugada syndrome are present in the same (affected) individuals, demonstrating that LQT3 and Brugada syndrome are more closely related than heretofore appreciated. Both syndromes can even be caused by the same mutation.
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Acknowledgments |
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This work was supported by Grant D95/014 from the Dutch Heart Foundation. We are indebted to the family members for their participation. We thank Dr Antoinette Groenewegen for help with the expression studies and helpful discussions. We thank Hester Cazemier, Muriël Blok, Joke Verheij, and Marriëtte Schipper for their help in establishing the pedigree and linkage analysis and for their efforts in collecting patient material. In addition, we are grateful to Drs J.H. Cornel (Medisch Centrum Alkmaar, the Netherlands), R.W. Breedveld (Medisch Centrum Leeuwarden, the Netherlands), M.R. van der Linde and J.J. de Graaf (Nij Smellinge, Drachten, the Netherlands), and E.W. van der Toren (Sionsberg, Dokkum, the Netherlands). Dr Dan Roden (Nashville, TN) is gratefully acknowledged for his critical reading of the manuscript.
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Footnotes |
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1 Both authors contributed equally to this study.
Received July 8, 1999; accepted September 26, 1999.
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N. Shirai, N. Makita, K. Sasaki, H. Yokoi, I. Sakuma, H. Sakurada, J. Akai, A. Kimura, M. Hiraoka, and A. Kitabatake A mutant cardiac sodium channel with multiple biophysical defects associated with overlapping clinical features of Brugada syndrome and cardiac conduction disease Cardiovasc Res, February 1, 2002; 53(2): 348 - 354. [Abstract] [Full Text] [PDF]
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R. Brugada and R. Roberts Brugada Syndrome: Why Are There Multiple Answers to a Simple Question? Circulation, December 18, 2001; 104(25): 3017 - 3019. [Full Text] [PDF]
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F. Kyndt, V. Probst, F. Potet, S. Demolombe, J.-C. Chevallier, I. Baro, J.-P. Moisan, P. Boisseau, J.-J. Schott, D. Escande, et al. Novel SCN5A Mutation Leading Either to Isolated Cardiac Conduction Defect or Brugada Syndrome in a Large French Family Circulation, December 18, 2001; 104(25): 3081 - 3086. [Abstract] [Full Text] [PDF]
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S Sangwatanaroj, S Prechawat, B Sunsaneewitayakul, S Sitthisook, P Tosukhowong, and K Tungsanga New electrocardiographic leads and the procainamide test for the detection of the Brugada sign in sudden unexplained death syndrome survivors and their relatives Eur. Heart J., December 2, 2001; 22(24): 2290 - 2296. [Abstract] [PDF]
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P Syrris, A Murray, N D Carter, W M McKenna, and S Jeffery Mutation detection in long QT syndrome: a comprehensive set of primers and PCR conditions J. Med. Genet., October 1, 2001; 38(10): 705 - 710. [Full Text] [PDF]
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P. C. Viswanathan, C. R. Bezzina, A. L. George Jr., D. M. Roden, A. A.M. Wilde, and J. R. Balser Gating-Dependent Mechanisms for Flecainide Action in SCN5A-Linked Arrhythmia Syndromes Circulation, September 4, 2001; 104(10): 1200 - 1205. [Abstract] [Full Text] [PDF]
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P. M. Spooner, C. Albert, E. J. Benjamin, R. Boineau, R. C. Elston, A. L. George Jr, X. Jouven, L. H. Kuller, J. W. MacCluer, E. Marban, et al. Sudden Cardiac Death, Genes, and Arrhythmogenesis : Consideration of New Population and Mechanistic Approaches From a National Heart, Lung, and Blood Institute Workshop, Part I Circulation, May 15, 2001; 103(19): 2361 - 2364. [Abstract] [Full Text] [PDF]
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I. Gussak, P. Bjerregaard, and S. C. Hammill Clinical diagnosis and risk stratification in patients with brugada syndrome J. Am. Coll. Cardiol., May 1, 2001; 37(6): 1635 - 1638. [Full Text] [PDF]
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C Antzelevitch The Brugada syndrome: diagnostic criteria and cellular mechanisms Eur. Heart J., March 1, 2001; 22(5): 356 - 363. [PDF]
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C. R Bezzina, M. B Rook, and A. A.M Wilde Cardiac sodium channel and inherited arrhythmia syndromes Cardiovasc Res, February 1, 2001; 49(2): 257 - 271. [Full Text] [PDF]
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X. Wan, S. Chen, A. Sadeghpour, Q. Wang, and G. E. Kirsch Accelerated inactivation in a mutant Na+ channel associated with idiopathic ventricular fibrillation Am J Physiol Heart Circ Physiol, January 1, 2001; 280(1): H354 - H360. [Abstract] [Full Text] [PDF]
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D. W. Wang, N. Makita, A. Kitabatake, J. R. Balser, and A. L. George Jr Enhanced Na+ Channel Intermediate Inactivation in Brugada Syndrome Circ. Res., October 13, 2000; 87 (8): e37 - e43. [Abstract] [Full Text] [PDF]
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I. Splawski, J. Shen, K. W. Timothy, M. H. Lehmann, S. Priori, J. L. Robinson, A. J. Moss, P. J. Schwartz, J. A. Towbin, G. M. Vincent, et al. Spectrum of Mutations in Long-QT Syndrome Genes : KVLQT1, HERG, SCN5A, KCNE1, and KCNE2 Circulation, September 5, 2000; 102(10): 1178 - 1185. [Abstract] [Full Text] [PDF]
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S. G. Priori, C. Napolitano, P. J. Schwartz, R. Bloise, L. Crotti, and E. Ronchetti The Elusive Link Between LQT3 and Brugada Syndrome : The Role of Flecainide Challenge Circulation, August 29, 2000; 102(9): 945 - 947. [Abstract] [Full Text] [PDF]
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H. Abriel, X. H. T. Wehrens, J. Benhorin, B. Kerem, and R. S. Kass Molecular Pharmacology of the Sodium Channel Mutation D1790G Linked to the Long-QT Syndrome Circulation, August 22, 2000; 102(8): 921 - 925. [Abstract] [Full Text] [PDF]
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C.-E. Chiang and D. M. Roden The long QT syndromes: genetic basis and clinical implications J. Am. Coll. Cardiol., July 1, 2000; 36(1): 1 - 12. [Abstract] [Full Text] [PDF]
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M. W. Veldkamp, P. C. Viswanathan, C. Bezzina, A. Baartscheer, A. A. M. Wilde, and J. R. Balser Two Distinct Congenital Arrhythmias Evoked by a Multidysfunctional Na+ Channel Circ. Res., May 12, 2000; 86 (9): e91 - e97. [Abstract] [Full Text] [PDF]
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A. A.M. Wilde and M. W. Veldkamp What we can learn from individual resuscitated patients Cardiovasc Res, April 1, 2000; 46(1): 14 - 16. [Full Text] [PDF]
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I. Rivolta, H. Abriel, M. Tateyama, H. Liu, M. Memmi, P. Vardas, C. Napolitano, S. G. Priori, and R. S. Kass Inherited Brugada and Long QT-3 Syndrome Mutations of a Single Residue of the Cardiac Sodium Channel Confer Distinct Channel and Clinical Phenotypes J. Biol. Chem., August 10, 2001; 276(33): 30623 - 30630. [Abstract] [Full Text] [PDF]
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H. Abriel, C. Cabo, X. H. T. Wehrens, I. Rivolta, H. K. Motoike, M. Memmi, C. Napolitano, S. G. Priori, and R. S. Kass Novel Arrhythmogenic Mechanism Revealed by a Long-QT Syndrome Mutation in the Cardiac Na+ Channel Circ. Res., April 13, 2001; 88(7): 740 - 745. [Abstract] [Full Text] [PDF]
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C. E. Clancy and Y. Rudy Na+ Channel Mutation That Causes Both Brugada and Long-QT Syndrome Phenotypes: A Simulation Study of Mechanism Circulation, March 12, 2002; 105(10): 1208 - 1213. [Abstract] [Full Text] [PDF]
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