(Circulation. 1999;99:3165-3171.)
© 1999 American Heart Association, Inc.
Clinical Investigation and Reports |
Congenital Long-QT Syndrome Caused by a Novel Mutation in a Conserved Acidic Domain of the Cardiac Na+ Channel
From the Departments of Medicine (J.W., D.M.R., A.L.G.), Pharmacology (D.W.W., D.M.R., A.L.G.), and Pediatrics (F.F.), Vanderbilt University School of Medicine, Nashville, Tenn, and the Academic Medical Center, University of Amsterdam, The Netherlands (M.A.).
Correspondence to Alfred L. George, Jr, 452 MRB-II, Vanderbilt University Medical Center, 23rd Ave S at Pierce Ave, Nashville, TN 37232. E-mail al.george{at}mcmail.vanderbilt.edu
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Abstract |
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Background—Congenital long-QT syndrome (LQTS) is an inherited condition of abnormal cardiac excitability characterized clinically by an increased risk of ventricular tachyarrhythmias. One form, LQT3, is caused by mutations in the cardiac voltage–dependent sodium channel gene, SCN5A. Only 5 SCN5A mutations have been associated with LQTS, and more work is needed to improve correlations between SCN5A genotypes and associated clinical syndromes.
Methods and Results—We researched a 3-generation white family with autosomal dominant LQTS who exhibited a wide clinical spectrum from mild bradycardia to sudden death. Molecular genetic studies revealed a single nucleotide substitution in SCN5A exon 28 that caused the substitution of Glu1784 by Lys (E1784K). The mutation occurs in a highly conserved domain within the C-terminus of the cardiac sodium channel containing multiple, negatively charged amino acids. Two-electrode voltage-clamp recordings of a recombinant E1784K mutant channel expressed in Xenopus oocytes revealed a defect in fast inactivation characterized by a small, persistent current during long membrane depolarizations. Coexpression of the mutant with the human sodium channel ß1-subunit did not affect the persistent current, even though we did observe shifts in the voltage dependence of steady-state inactivation. Neutralizing multiple, negatively charged residues in the same region of the sodium channel C-terminus did not cause a more severe functional defect.
Conclusions—We characterized the genetics and molecular pathophysiology of a novel SCN5A sodium channel mutation, E1784K. The functional defect exhibited by the mutant channel causes delayed myocardial repolarization, and our data on the effects of multiple charge neutralizations in this region of the C-terminus suggest that the molecular mechanism of channel dysfunction involves an allosteric rather than a direct effect on channel gating.
Key Words: long-QT syndrome • sodium channel • SCN5A • genes • heart defects, congenital
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Introduction |
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Congenital long-QT syndrome (LQTS) is an inherited condition of abnormal cardiac excitability characterized clinically by an increased risk of potentially fatal ventricular tachyarrhythmias, especially torsades de pointes.1 2 3 The syndrome is most often transmitted in families as an autosomal-dominant trait (Romano-Ward syndrome) and less commonly as a recessive illness combined with congenital deafness. LQTS derives its name from the characteristic prolongation of the QT interval on surface electrocardiograms of affected individuals, correlating with an increased duration of the ventricular action potential caused by an increase in the time required for myocardial cell repolarization. Congenital LQTS is an important disease model for understanding cardiac electrophysiology and the basic mechanisms underlying cardiac arrhythmias, including drug-induced LQTS, a major therapeutic obstacle to the safe use of many antiarrhythmic agents.4 Therefore, a more thorough understanding of the molecular basis of LQTS may lead to the development of more effective therapeutic strategies to prevent the widespread problem of sudden cardiac death.
Recent work on the molecular genetics of LQTS has demonstrated that it
is an inherited disorder of cardiac ion channels.1 2 3 The
majority of LQTS subjects seem to harbor mutations in 2 cardiac
potassium channel genes (HERG and
KvLQT1),5 6 but additional cases are
caused by mutations in genes encoding a potassium channel regulatory
subunit (KCNE1),7 a cardiac
voltage–dependent sodium channel 
-subunit
(SCN5A),8 and other unidentified gene
products.9 Preliminary
genotype-phenotype correlations have suggested that
sodium channel mutations may produce distinct clinical features in LQTS
patients, including bradycardia, exercise-induced QT shortening, and
mexiletine responsiveness.3 10 To date, there have been
only 5 identified SCN5A mutations associated with
LQTS,8 11 12 13 and further work is needed to bolster
those preliminary observations regarding the clinical and molecular
aspects of the syndrome.
We report here the identification of a novel SCN5A mutation in autosomal-dominant LQTS. The mutation occurs in a highly conserved acidic domain within the carboxy terminus of the cardiac sodium channel and produces subtle gating abnormalities that are the likely cause of the disease. Results from additional mutagenesis experiments in this domain suggest that the biophysical mechanism may be allosteric rather than caused by direct interference with channel-gating processes. Our results provide additional molecular genetic and pathophysiological observations regarding LQTS and normal sodium channel physiology and contribute to our understanding of sudden cardiac death.
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Methods |
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Patients
A 3-generation white family with autosomal-dominant LQTS was identified after the witnessed sudden death of the proband, a 13-year-old girl with no prior illnesses (Figure 1
). The proband died while at rest. An
autopsy demonstrated no evidence of structural heart disease. Two
siblings and both parents were available for clinical evaluation of the
immediate family. The father experienced occasional light-headedness
and had 1 episode of syncope 9 years before evaluation, but he denied
palpitations or recent syncope. The proband's mother and both siblings
were asymptomatic. A paternal aunt had died suddenly at the
age of 42 years of an unknown cause. ECGs of the father revealed sinus
bradycardia (32 bpm), prominent U waves in the right precordial
leads, and profound prolongation of the rate-corrected QT interval
(QTc=527 ms). A 24-hour ECG recording in the father
demonstrated intermittent ventricular ectopy during
bradycardic episodes and occasional sinus pauses, prompting insertion
of a dual-chamber pacemaker. His living daughter's resting ECG also
revealed isoelectric ST segments and slightly prolonged QTc intervals
in several leads (maximum QTc=464 ms). During an exercise treadmill
test, her QTc interval shortened to 400 ms (10 minutes, stage 4 Bruce
protocol; heart rate, 163 bpm) from a preexercise baseline of 486 ms
(heart rate, 77 bpm) and then prolonged to 492 ms during the recovery
phase (5 minutes after exercise; heart rate, 113 bpm). ECGs of the
mother and son were normal.
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Additional members of the extended family were examined clinically for the presence of LQTS. One paternal uncle experienced syncope during childhood but was asymptomatic in adulthood. His son was asymptomatic. Both individuals exhibited sinus bradycardia and QT prolongation. Other members of the extended family were either unavailable or had normal QT intervals.
Molecular Genetics
Informed consent was obtained from participating family members
using a method approved by the Vanderbilt University Institutional
Review Board. Genomic DNA was isolated from peripheral
blood leukocytes using standard methods.14 Selected
SCN5A exons were screened for the presence of
nucleotide sequence polymorphisms by single-strand
conformation analysis. Oligonucleotide primer
pairs, as described by Wang et al,15 were used to
amplify SCN5A exons 16 through 28 using polymerase chain
reaction (PCR). Primers used to amplify the SCN5A-coding
region containing nucleotides 5229 to 5538 were
5'-GAGCCCAGCCGTGGGCATCCT-3' (forward primer) and
5'-GTCCCCACTCACCATGGGCAG-3' (reverse primer). Amplification reactions
were carried out using 200 ng of genomic DNA, 0.5 µmol/L of
primers, 0.2 mmol/L dNTPs, and Taq polymerase.
Single-strand conformation analysis was performed on 0.5x MDE
gels that were electrophoresed overnight at 4 W and stained with silver
nitrate. Abnormal conformers were excised from dried gels, eluted into
sterile water, reamplified using the original primers, and sequenced
using dye-terminator chemistry. The presence of the specific mutation
(E1784K) reported in this study was confirmed independently on
PCR-amplified genomic DNA using an allele-specific
oligonucleotide hybridization assay with a
32P end-labeled primer
(5'-AGAGCACCAAGCCCCTG-3').
Site-Directed Mutagenesis
Mutagenesis of human cardiac sodium channel -subunit cDNA
(hH1)16 using a 1-step recombinant PCR strategy was
performed to create the E1784K mutation. A forward primer
(5'-GTGGTCAAC-ATGTACATTGCCATCATCCTGGAGAACTTC
AGCGTGGCC-ACGGAGGAGAGTACTAAGCCCCTGAGTGAGGACGA-3')
spanning nucleotides 5287 to 5369 and the reverse primer
described above were used to create the mutation (the changed codon is
underlined) and incorporate natural restriction sites for
BsrGI (nucleotide 5298) and AspEI
(nucleotide 5461) in the final 252-bp product.
Amplifications (20 cycles) were performed using 20 ng of hH1 cDNA as a
template and Taq DNA polymerase. Final products were
purified by spin-column chromatography (Qiagen) and
digested with BsrGI and AspEI; the resulting
164-bp fragment was ligated into the corresponding sites in the plasmid
pSP64T-hH1. The amplified region was sequenced entirely in the final
construct to verify the mutation and to exclude polymerase errors.
Additional hH1 mutations were constructed using a similar approach. One mutation (Q-I) consisting of 4 Gln substitutions for Glu at positions 1773, 1780, 1781, and 1784 was constructed using the forward primer 5'-GTGGTCAACATGTACATTGCCATCATCCTGCAGAAC TTCAGCGTGGCCACGCAGCAGAGTACTCAGCC-CCTGAGTGAGGACGA-3' (changed codons are underlined) and the previously described reverse primer. A second, multiple charge-neutralizing mutation (Q-II) was constructed in which Gln substitutions were made for negatively charged amino acids at positions 1788, 1789, 1790, and 1792 using the mutagenic forward primer 5'-AGCACCGAGCCCCTGAGTCAACAGCAGTTCCAGATGTT-CTATGAGATCTGG-3' (changed codons are underlined). Subcloning of Q-I and Q-II mutant fragments was performed as described for E1784K.
Electrophysiology
All cDNAs encoding wild-type and mutant hH1 were transcribed in
vitro from pSP64T constructs using SP6 RNA polymerase, and the
resultant cRNAs were microinjected into Xenopus oocytes. In
most experiments, coexpression with a recombinant human
ß1-subunit (hß1) was
achieved by coinjecting oocytes with cRNA derived from the plasmid
pSP64T-hß1.17 Sodium channel
expression was examined by 2-microelectrode voltage-clamp
recording, as previously described.18 19 20 All
measurements were made using the pCLAMP suite of programs (Axon
Instruments) and analyzed as previously
described.21 For measurements of tetrodotoxin
(TTX)-sensitive current, recordings were made during repetitive
200-ms test pulses to -20 mV from a holding potential of -120 mV
(interpulse duration was 5 s) in the absence and presence of
30 µmol/L of TTX. The average current was obtained 20 to 30
records after achieving steady state, and the difference between
the presence and absence of TTX was used as the TTX-sensitive current
component. TTX-sensitive currents were recorded from 4 to 6 oocytes
for each mutation.
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Results |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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Molecular Genetics
Because of the clinical findings of bradycardia and exercise-induced QT-interval shortening observed in the LQTS family, we chose to screen selected regions of the SCN5A coding region for nucleotide sequence variants. Initially, exon segments containing previously identified mutations were evaluated by single-strand conformational analysis, but they were normal. We next initiated a systematic screen of additional SCN5A exons, beginning first with regions encoding the fourth domain (D4) and carboxy terminus. Examination of the coding region between the D4/S6 segment and the early C-terminus demonstrated an aberrant single-strand conformer in affected individuals from this family but not in unaffected members (Figure 2
).
Nucleotide sequencing of the aberrant product revealed
a G
A transition associated with a codon change (GAG to AAG),
predicting the substitution of Glu1784 by Lys (designated E1784K). This
nucleotide change was independently confirmed in all
affected, but none of the unaffected, members of the family using an
allele-specific oligonucleotide hybridization
assay. The mutation was also not detected in 100 normal control DNA
samples using this same assay. The cosegregation of the allele with
the disease phenotype, its absence in the general population,
and the resulting nonconservative amino acid substitution are
consistent with a disease-producing mutation.
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The affected residue (Glu1784) is located within a highly conserved
acidic domain immediately following the D4/S6 segment. Glu or, rarely,
Asp is found at this corresponding location in most voltage-gated
sodium channel sequences in most animals, including
invertebrates (Figure 3). Further
inspection reveals that this region of the early C-terminus has
clusters of negatively charged amino acid residues. A similar motif is
also found in the corresponding region of L-type calcium channels, and
it has a remote homology to an EF-hand
Ca2+ binding motif.22 23 The
functional importance of this region in sodium channels has not been
explored.
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). E1784K mutation
reported here is boxed. Amino acid–sequence alignments of
SCN5A with related sodium channel sequences are shown in
lower panel (SCN5A, human heart [M77235]; SCN2A, human brain type II
[M94055]; SCN4A, human skeletal muscle [M81758]; SCN1A, rat brain
type I [M22253]; Fly, Drosophila para locus
[M24285]; Eel, eel electroplax [M22252]; GenBank accession numbers
given in square brackets).
Functional Characterization of E1784K
We used the Xenopus oocyte expression system and
2-electrode voltage-clamp recording to evaluate the functional
consequences of the E1784K mutation engineered into a recombinant human
cardiac sodium channel -subunit (hH1). Expression of wild-type (WT)
and mutant hH1 in oocytes gave rise to sodium currents of similar
magnitude. Initial inspection of raw current traces obtained in
response to depolarizing test potentials seemed similar between WT-hH1
and E1784K. However, when TTX-sensitive sodium currents were
analyzed, a small (2% to 4%) residual current was observed in
oocytes expressing E1784K but not WT-hH1. Coexpression of
hß1 had no effect on the presence or magnitude
of this residual current (Figure 4). This
is best illustrated with an expanded current scale, as shown in
Figure 4, C and D. The occurrence of a
noninactivating steady-state current throughout
long depolarizations has been observed with other SCN5A
mutations associated with congenital LQTS,24 25 26 and
it is consistent with a disease-producing lesion.
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The apparent defect in channel inactivation was further quantified by
fitting the decay phase of both WT-hH1 and E1784K current traces with
double exponential functions. Time constants for the fast phase of
inactivation were indistinguishable (
fast,
WT-hH1=1.3±0.06, n=10, versus E1784K=1.3±0.06, n=23), but the time
constant of the slow component was significantly larger in the mutant
(slow, WT-hH1=12.1±0.33 versus
E1784K=22.4±1.55; P<0.001). Coexpression with
hß1 produced currents that differed
significantly in the fast time constant of inactivation, largely
because of an effect on E1784K (fast,
WT-hH1=1.2±0.03, n=31, versus E1784K=0.94±0.03, n=39;
P<0.0001). Steady-state inactivation (Figure 5A) was also altered in the mutant, with
a significant shift in the midpoint of steady-state inactivation
(V1/2) toward more negative potentials in the
absence of hß1 (V1/2,
WT-hH1=-74.0±0.9 mV, n=7, versus E1784K=-79.3±0.5 mV, n=20;
P<0.001). Coexpression with hß1
exaggerated this negative shift in V1/2
(V1/2,
WT-hH1+hß1=-63.2±1.3 mV, n=10, versus
E1784K+hß1=-75.3±0.9 mV, n=11;
P<0.01). We also observed a small but significant change in
the time course of recovery from inactivation elicited by a 500-ms
prepulse (Figure 5B). The functional disturbances
observed with oocytes expressing E1784K are similar to previously
observed functional defects in 3 other LQTS SCN5A
mutations24 25 26 and are consistent with a
molecular lesion being responsible for the disease.
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Structure-Function Relationships
As discussed above, the highly conserved acidic domain within the
early portion of the hH1 carboxy terminus has no known function.
Because mutations in this region cause disease-producing channel
dysfunction, we hypothesized that this structure might participate in
channel gating. To evaluate this hypothesis, we neutralized clusters of
acidic residues surrounding Glu1784 and studied their functional
behavior in oocytes. Figure 6
illustrates the strategy used to make 2-charge neutralizing mutants and
their corresponding whole cell recordings. The first mutant
construct, Q-I, consists of 4 Gln substitutions for Glu at positions
1773, 1780, 1781, and 1784. Functional characterization of this mutant
revealed a pattern of channel gating similar to E1784K. Specifically,
Q-I exhibits a small, noninactivating current
component during long test depolarizations (Figure 6) and a negative
shift in steady-state inactivation but no difference in the time course
of recovery from inactivation (Figure 7). Additional Gln substitutions
of the C-terminal to Glu1784 (mutant Q-II), including substitutions at
positions 1788 through 1790 and 1792, produced a similar
phenotype. The absence of more severe gating
disturbances associated with the multiple-charge
neutralizations strongly suggest that residues within this highly
conserved acidic domain do not participate directly in the gating
process.
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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In this article, we describe a novel mutation in the human cardiac sodium channel
-subunit gene (SCN5A) that causes
autosomal-dominant congenital LQTS. Relatively few SCN5A mutations have
been identified compared with the striking allelic
heterogeneity found in the 2 cardiac potassium channel
genes (HERG and KvLQT1) responsible for the
majority of congenital LQTS cases. Although SCN5A is a much
larger gene than either of the 2 cardiac potassium channel genes, the
coding sequences of HERG and KvLQT1 are rich in
CpG dinucleotides that are potential hot spots for
mutations. It is important to make correlations between molecular
genotype and the associated clinical syndrome to develop
predictive markers for disease and help guide the most appropriate
therapy. The family we described has certain characteristics that have been associated with other SCN5A-linked forms of congenital LQTS, including bradycardia, exercise-induced QT-interval shortening, and isoelectric ST-T wave segments.3 The other important clinical observation in this family, as well as in many other families with LQTS, is the surprising lack of symptoms and objective manifestations of the disease in certain ECG- and genotype-positive individuals. This observation raises the prospect of gene-environmental interactions as important disease precipitants or the involvement of modifier genes in causing the phenotype. Clearly, more work is required to elucidate the basis for disease latency in such individuals.
The mutation we describe in this article (E1784K) occurs in a highly
conserved acidic domain located in the early carboxy terminal segment
of the sodium channel protein. This region has received little
attention from sodium channel investigators, although there are now 3
known naturally occurring allelic variants within this domain in 2
distinct sodium channel isoforms.13 27 The first variant,
described by Wang et al,27 occurs in the skeletal
muscle sodium -subunit gene (SCN4A) and is associated
with autosomal-dominant hyperkalemic periodic paralysis in a large
Yugoslavian family. The allelic variant causes substitution of Lys for
Glu1606 in SCN4A, only a few amino acids away from the
corresponding residues in SCN5A that cause LQTS when
substituted (E1784K, D1790G).13 The functional
characterization of the skeletal-muscle sodium channel allele has
not yet been reported. The functional characterization of the
SCN5A allele reported by An et al13
(Asp1790Gly, or D1790G) has recently been described. This
mutation causes little overt gating disturbances in recombinant
cardiac sodium channels expressed in a cultured mammalian cell line.
Rather, this mutation exhibits subtle differences in the voltage
dependence of inactivation that are accentuated by coexpression with
the accessory ß1-subunit.13 It is
less clear how this pattern of dysfunction leads to delayed myocardial
repolarization and LQTS, and it is difficult to reconcile with the work
of several groups demonstrating that the cytoplasmic domain of the
ß1-subunit is not required for its functional
effects on mammalian sodium channels.17 28 29 Nonetheless,
the accentuation of the functional defect by the
ß1 subunit is also apparent in our work on
E1784K.
The functional characteristics of E1784K closely resemble the gating disturbances observed for many other SCN5A LQTS mutations.24 25 26 This defect is characterized by a small, persistent, inward current during long depolarizations that is expected to contribute to the delay in myocardial repolarization. The molecular basis for this channel dysfunction could involve direct interference with closure of the inactivation gate in the channel or involve indirect mechanisms that disrupt the critical conformational changes necessary for complete inactivation. However, it is not possible to assign a molecular mechanism solely on the basis of the results of a single-point mutation. Therefore, we tested the effects of additional structural changes in the highly conserved acidic domain to explore whether this structure participates directly in sodium channel gating. Our results suggest that neutralizing up to 4 negatively charged groups in this domain has little or no additional effect on the gating disturbance observed with the single-charge reversal mutation. These data argue in favor of an allosteric mechanism for channel dysfunction produced by both the disease-associated mutant and the multiply charged neutralization mutations.
In summary, we report the role of a novel SCN5A missense mutation in causing congenital LQTS and provide evidence that the functional basis for this disease-producing allele involves an allosteric effect on sodium channel gating. This work further emphasizes the importance of performing additional structure-function analyses before making conclusions about the direct involvement of mutated structures in channel behavior.
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Acknowledgments |
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The authors thank members of the family for their willing participation in this study; Kris Norris, RN, for family ascertainment; and Craig Short for DNA sequencing. This work was supported by NIH grants NS32387 (A.L.G.) and HL46681 (D.R.). J.W. was supported by an institutional training grant (T32 DK07569). M.A. is the recipient of a fellowship award from the Interuniversity Cardiology Institute of the Netherlands. A.L.G. is an Established Investigator of the American Heart Association.
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Footnotes |
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The first 2 authors contributed equally to this work.
The present address for M. Alings is Snodenhoekpark 21, 1107 VD Amsterdam, Netherlands.
Received December 31, 1998; revision received March 30, 1999; accepted March 31, 1999.
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 E. R. Behr, C. Dalageorgou, M. Christiansen, P. Syrris, S. Hughes, M. T. Tome Esteban, E. Rowland, S. Jeffery, and W. J. McKenna Sudden arrhythmic death syndrome: familial evaluation identifies inheritable heart disease in the majority of families Eur. Heart J., July 1, 2008; 29(13): 1670 - 1680. [Abstract] [Full Text] [PDF]
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 H. H. Zakon, D. J. Zwickl, Y. Lu, and D. M. Hillis Molecular evolution of communication signals in electric fish J. Exp. Biol., June 1, 2008; 211(11): 1814 - 1818. [Abstract] [Full Text] [PDF]
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 D. W. Wang, R. R. Desai, L. Crotti, M. Arnestad, R. Insolia, M. Pedrazzini, C. Ferrandi, A. Vege, T. Rognum, P. J. Schwartz, et al. Cardiac Sodium Channel Dysfunction in Sudden Infant Death Syndrome Circulation, January 23, 2007; 115(3): 368 - 376. [Abstract] [Full Text] [PDF]
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 J. M. Nerbonne and R. S. Kass Molecular Physiology of Cardiac Repolarization Physiol Rev, October 1, 2005; 85(4): 1205 - 1253. [Abstract] [Full Text] [PDF]
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W. Ulbricht Sodium Channel Inactivation: Molecular Determinants and Modulation Physiol Rev, October 1, 2005; 85(4): 1271 - 1301. [Abstract] [Full Text] [PDF]
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 L.S. Meadows and L.L. Isom Sodium channels as macromolecular complexes: Implications for inherited arrhythmia syndromes Cardiovasc Res, August 15, 2005; 67(3): 448 - 458. [Abstract] [Full Text] [PDF]
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 T. Chen, M. Inoue, and M. F. Sheets Reduced voltage dependence of inactivation in the SCN5A sodium channel mutation delF1617 Am J Physiol Heart Circ Physiol, June 1, 2005; 288(6): H2666 - H2676. [Abstract] [Full Text] [PDF]
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 H. K. Motoike, H. Liu, I. W. Glaaser, A.-S. Yang, M. Tateyama, and R. S. Kass The Na+ Channel Inactivation Gate Is a Molecular Complex: A Novel Role of the COOH-terminal Domain J. Gen. Physiol., January 26, 2004; 123(2): 155 - 165. [Abstract] [Full Text] [PDF]
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 M. W. Veldkamp, R. Wilders, A. Baartscheer, J. G. Zegers, C. R. Bezzina, and A. A.M. Wilde Contribution of Sodium Channel Mutations to Bradycardia and Sinus Node Dysfunction in LQT3 Families Circ. Res., May 16, 2003; 92(9): 976 - 983. [Abstract] [Full Text] [PDF]
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H. L Tan, C. R Bezzina, J. P.P Smits, A. O Verkerk, and A. A.M Wilde Genetic control of sodium channel function Cardiovasc Res, March 15, 2003; 57(4): 961 - 973. [Abstract] [Full Text] [PDF]
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W.A. Groenewegen, C. R. Bezzina, J.P. van Tintelen, T. M. Hoorntje, M. M.A.M. Mannens, A. A.M. Wilde, Habo.J. Jongsma, and M. B. Rook A novel LQT3 mutation implicates the human cardiac sodium channel domain IVS6 in inactivation kinetics Cardiovasc Res, March 15, 2003; 57(4): 1072 - 1078. [Abstract] [Full Text] [PDF]
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C.-j. Liu, S. D. Dib-Hajj, M. Renganathan, T. R. Cummins, and S. G. Waxman Modulation of the Cardiac Sodium Channel Nav1.5 by Fibroblast Growth Factor Homologous Factor 1B J. Biol. Chem., January 3, 2003; 278(2): 1029 - 1036. [Abstract] [Full Text] [PDF]
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 E. Moric, E. Herbert, M. Trusz-Gluza, A. Filipecki, U. Mazurek, and T. Wilczok The implications of genetic mutations in the sodium channel gene (SCN5A) Europace, January 1, 2003; 5(4): 325 - 334. [Abstract] [Full Text] [PDF]
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 H. Denac, M. Mevissen, F. J. P. Kuhn, C. Kuhn, C. T. Guionaud, G. Scholtysik, and N. G. Greeff Molecular Cloning and Functional Characterization of a Unique Mammalian Cardiac Nav Channel Isoform with Low Sensitivity to the Synthetic Inactivation Inhibitor (-)-(S)-6-Amino-alpha -[(4-diphenylmethyl-1-piperazinyl)-methyl]-9H-purine-9-ethanol (SDZ 211-939) J. Pharmacol. Exp. Ther., October 1, 2002; 303(1): 89 - 98. [Abstract] [Full Text] [PDF]
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H. Liu, M. Tateyama, C. E. Clancy, H. Abriel, and R. S. Kass Channel Openings Are Necessary but not Sufficient for Use-dependent Block of Cardiac Na+ Channels by Flecainide: Evidence from the Analysis of Disease-linked Mutations J. Gen. Physiol., June 24, 2002; 120(1): 39 - 51. [Abstract] [Full Text] [PDF]
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J. W. Cormier, I. Rivolta, M. Tateyama, A.-S. Yang, and R. S. Kass Secondary Structure of the Human Cardiac Na+ Channel C Terminus. EVIDENCE FOR A ROLE OF HELICAL STRUCTURES IN MODULATION OF CHANNEL INACTIVATION J. Biol. Chem., March 8, 2002; 277(11): 9233 - 9241. [Abstract] [Full Text] [PDF]
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I. Deschenes, N. Neyroud, D. DiSilvestre, E. Marban, D. T. Yue, and G. F. Tomaselli Isoform-Specific Modulation of Voltage-Gated Na+ Channels by Calmodulin Circ. Res., March 8, 2002; 90 (4): e49 - e57. [Abstract] [Full Text] [PDF]
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 E. S Bennett Isoform-specific effects of sialic acid on voltage-dependent Na+ channel gating: functional sialic acids are localized to the S5-S6 loop of domain I J. Physiol., February 1, 2002; 538(3): 675 - 690. [Abstract] [Full Text] [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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H. Wedekind, J. P.P. Smits, E. Schulze-Bahr, R. Arnold, M. W. Veldkamp, T. Bajanowski, M. Borggrefe, B. Brinkmann, I. Warnecke, H. Funke, et al. De Novo Mutation in the SCN5A Gene Associated With Early Onset of Sudden Infant Death Circulation, September 4, 2001; 104(10): 1158 - 1164. [Abstract] [Full Text] [PDF]
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E. S Bennett Channel cytoplasmic loops alter voltage-dependent sodium channel activation in an isoform-specific manner J. Physiol., September 1, 2001; 535(2): 371 - 381. [Abstract] [Full Text] [PDF]
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J.M. Lupoglazoff, T. Cheav, G. Baroudi, M. Berthet, I. Denjoy, B. Cauchemez, F. Extramiana, M. Chahine, and P. Guicheney Homozygous SCN5A Mutation in Long-QT Syndrome With Functional Two-to-One Atrioventricular Block Circ. Res., July 20, 2001; 89 (2): e16 - e21. [Abstract] [Full Text] [PDF]
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 J. A. Towbin, Z. Wang, and H. Li Genotype and Severity of Long QT Syndrome Drug Metab. Dispos., April 1, 2001; 29(4): 574 - 579. [Abstract] [Full Text]
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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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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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X. H. T. Wehrens, H. Abriel, C. Cabo, J. Benhorin, and R. S. Kass Arrhythmogenic Mechanism of an LQT-3 Mutation of the Human Heart Na+ Channel {alpha}-Subunit : A Computational Analysis Circulation, August 1, 2000; 102(5): 584 - 590. [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. Deschenes, G. Baroudi, M. Berthet, I. Barde, T. Chalvidan, I. Denjoy, P. Guicheney, and M. Chahine Electrophysiological characterization of SCN5A mutations causing long QT (E1784K) and Brugada (R1512W and R1432G) syndromes Cardiovasc Res, April 1, 2000; 46(1): 55 - 65. [Abstract] [Full Text] [PDF]
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C. Bezzina, M. W. Veldkamp, M. P. van den Berg, A. V. Postma, M. B. Rook, J.-W. Viersma, I. M. van Langen, G. Tan-Sindhunata, M. Th. E. Bink-Boelkens, A. H. van der Hout, et al. A Single Na+ Channel Mutation Causing Both Long-QT and Brugada Syndromes Circ. Res., December 3, 1999; 85(12): 1206 - 1213. [Abstract] [Full Text] [PDF]
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M. B. Rook, C. Bezzina Alshinawi, W.A. Groenewegen, I. C. van Gelder, A. C.G. van Ginneken, H. J. Jongsma, M. M.A.M. Mannens, and A. A.M. Wilde Human SCN5A gene mutations alter cardiac sodium channel kinetics and are associated with the Brugada syndrome Cardiovasc Res, December 1, 1999; 44(3): 507 - 517. [Abstract] [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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F. G. Akar, G.-X. Yan, C. Antzelevitch, and D. S. Rosenbaum Unique Topographical Distribution of M Cells Underlies Reentrant Mechanism of Torsade de Pointes in the Long-QT Syndrome Circulation, March 12, 2002; 105(10): 1247 - 1253. [Abstract] [Full Text] [PDF]
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