(Circulation. 2000;102:1178.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Spectrum of Mutations in Long-QT Syndrome Genes
KVLQT1, HERG, SCN5A, KCNE1, and KCNE2
From the Department of Human Genetics (I.S., K.W.T., M.T.K.), Howard Hughes Medical Institute (J.S., M.T.K.), and Division of Cardiology (M.T.K.), University of Utah, and the Department of Medicine, LDS Hospital (G.M.V.), Salt Lake City, Utah; Department of Internal Medicine, University of Michigan, Ann Arbor (M.H.L.); Molecular Cardiology, Fondazione Maugeri (S.P.), and Department of Cardiology, University of Pavia and Policlinico S. Matteo (P.J.S.), IRCCS, Pavia, Italy; Department of Medicine, University of Rochester, Rochester, NY (J.L.R., A.J.M.); and Departments of Pediatrics and Molecular and Human Genetics (J.A.T.), Baylor College of Medicine, Houston, Tex.
Correspondence to Igor Splawski, University of Utah, Eccles Institute of Human Genetics, 15N 2030E Suite 2100, Salt Lake City, UT 84112-5330. E-mail igor.splawski{at}genetics.utah.edu
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Abstract |
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Background—Long-QT Syndrome (LQTS) is a cardiovascular disorder characterized by prolongation of the QT interval on ECG and presence of syncope, seizures, and sudden death. Five genes have been implicated in Romano-Ward syndrome, the autosomal dominant form of LQTS: KVLQT1, HERG, SCN5A, KCNE1, and KCNE2. Mutations in KVLQT1 and KCNE1 also cause the Jervell and Lange-Nielsen syndrome, a form of LQTS associated with deafness, a phenotypic abnormality inherited in an autosomal recessive fashion.
Methods and Results—We used mutational analyses to screen a pool of 262 unrelated individuals with LQTS for mutations in the 5 defined genes. We identified 134 mutations in addition to the 43 that we previously reported. Eighty of the mutations were novel. The total number of mutations in this population is now 177 (68% of individuals).
Conclusions—KVLQT1 (42%) and HERG (45%) accounted for 87% of identified mutations, and SCN5A (8%), KCNE1 (3%), and KCNE2 (2%) accounted for the other 13%. Missense mutations were most common (72%), followed by frameshift mutations (10%), in-frame deletions, and nonsense and splice-site mutations (5% to 7% each). Most mutations resided in intracellular (52%) and transmembrane (30%) domains; 12% were found in pore and 6% in extracellular segments. In most cases (78%), a mutation was found in a single family or an individual.
Key Words: long-QT syndrome • arrhythmia • death, sudden • torsade de pointes • genetics
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Introduction |
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Long-QT syndrome (LQTS) is a cardiovascular disorder characterized by an abnormality in cardiac repolarization leading to a prolonged QT interval on the surface ECG. LQTS causes syncope, seizures, and sudden death, usually in young, otherwise healthy individuals.1 2 3 The clinical features of LQTS result from episodic ventricular tachyarrhythmias, such as torsade de pointes and ventricular fibrillation.4 5 Two inherited forms of LQTS exist. The more common form, Romano-Ward syndrome, is not associated with other phenotypic abnormalities and is inherited as an autosomal dominant trait with variable penetrance.2 3 Jervell and Lange-Nielsen syndrome is characterized by the presence of deafness, a phenotypic abnormality inherited as an autosomal recessive trait.1 LQTS can also be acquired, usually as a result of pharmacological therapy.
In previous studies, we mapped LQTS loci to chromosomes 11p15.5
(LQT1),6 7q35-36
(LQT2),7 and 3p21-24
(LQT3).7 A fourth locus
(LQT4) was mapped to 4q25-27.8 Our
molecular genetic studies identified 5 genes: KVLQT1
(LQT1),9 HERG
(LQT2),10 SCN5A
(LQT3),11 and 2 genes located at
21q22, KCNE1 (LQT5)12 and
KCNE2 (LQT6).13
KVLQT1, HERG, KCNE1, and
KCNE2 encode potassium channel subunits. Four KVLQT1
-subunits assemble with minK (ß-subunits encoded by
KCNE1, stoichiometry is unknown) to form
IKs channels underlying the slowly
activating delayed rectifier potassium current in the
heart.14 15 Four HERG -subunits assemble with
MiRP1 (encoded by KCNE2, stoichiometry unknown) to form
IKr channels, which underlie the rapidly
activating, delayed rectifier potassium current.13
Mutant subunits lead to reduction of IKs or
IKr by a loss-of-function mechanism, often
with a dominant-negative effect.16 17 18 19
SCN5A encodes the cardiac sodium channel that is responsible
for INa, the sodium current in the
heart.20 LQTS-associated mutations in
SCN5A cause a gain of function.21 22 In
the heart, reduced IKs or
IKr or increased
INa leads to prolongation of the cardiac
action potential, lengthening of the QT interval, and increased risk of
arrhythmia. KVLQT1 and KCNE1 are also
expressed in the inner ear.23 24 We and others have
demonstrated that complete loss of IKs
causes the severe cardiac phenotype and deafness in Jervell and
Lange-Nielsen syndrome.23 25 26 27
Presymptomatic diagnosis of LQTS is currently based on prolongation of the QT interval on ECG. Genetic studies, however, have shown that diagnosis based solely on ECG is neither sensitive nor specific.28 29 Genetic screening using mutational analysis can improve presymptomatic diagnosis. However, no comprehensive study identifying and cataloging all LQTS-associated mutations in all 5 genes has been done. To determine the relative frequency of mutations in each gene, facilitate presymptomatic diagnosis, and allow genotype-phenotype studies, we screened a pool of 262 unrelated individuals with LQTS for mutations in the 5 defined genes.
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Methods |
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Ascertainment and Phenotyping
Individuals were ascertained in clinics from North America and Europe. They were evaluated for LQTS on the basis of QTc (the QT interval corrected for heart rate) and the presence of symptoms. In this study, we focused on the probands. Individuals show prolongation of the QT interval (QTc
460 ms) and/or documented torsade de pointes,
ventricular fibrillation, cardiac arrest, or aborted sudden
death. Informed consent was obtained in accordance with local
institutional review board guidelines. Phenotypic data were interpreted
without knowledge of genotype. Sequence changes altering coding
regions or predicted to affect splicing that were not detected in 400
control chromosomes were defined as mutations. No changes except known
polymorphisms were detected in any of the genes in the control
population. This does not exclude the possibility that some mutations
are rare variants not associated with disease.
Mutational Analyses
To determine the spectrum of LQTS mutations, we used
single strand conformation polymorphism (SSCP) and DNA sequence
analyses to screen 262 unrelated individuals with LQTS.
Seventeen primer pairs were used to screen
KVLQT1,30 21 primer pairs were used
for HERG,30 and 3 primer pairs were
used for KCNE112 and
KCNE2.13 Thirty-three primer
pairs31 were used in SSCP analysis to screen all
SCN5A exons in 50 individuals with suspected abnormalities
in INa. Exons 23 to 28, in which mutations
were previously identified, were screened in all 262 individuals.
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Results |
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We ascertained and phenotyped 262 individuals with LQTS. Sex, age, QTc, and presence of symptoms are summarized in Table 1
. The average age at
ascertainment was 29 years, and the corrected QT interval was 492 ms.
Seventy-five percent had a history of symptoms, and females
predominated, with an 
2:1 ratio. Although the numbers were small,
corrected QT intervals for individuals harboring KCNE1 and
KCNE2 mutations were shorter, at 457 ms.
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To determine the spectrum of mutations in these individuals, we
performed SSCP analyses. KVLQT1 mutations associated
with LQTS were identified in 52 individuals (Figure 1, Table 2. Twenty of the mutations were novel.
HERG mutations were identified in 68 LQTS individuals
(Figure 2, Table 3. Fifty-two of these mutations were
novel. SCN5A mutations were identified in 8 cases (Figure 3, Table 4). Five of the mutations were novel.
Three novel KCNE1 mutations were identified (Figure 4, Table 5), and 3 mutations were identified in
KCNE2 (Figure 5, Table 6).13 None of
the KVLQT1,
HERG, SCN5A, KCNE1, or
KCNE2 mutations were observed in 400 control
chromosomes.
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Previous studies had defined 126 distinct disease-causing mutations in the LQTS genes KVLQT1, HERG, SCN5A, KCNE1, and KCNE2 (Tables 3 to 7
).*
Most of them were found in KVLQT1 (n=66) and HERG
(n=41), and fewer in SCN5A (n=9), KCNE1 (n=7),
and KCNE2 (n=3). These mutations were identified in regions
with known intron/exon structure, primarily the transmembrane and pore
domains. In this study, we screened 262 individuals with LQTS for
mutations in all known arrhythmia genes. We identified 134
mutations, 80 of which were novel (Tables 2 to 6). Together with 43 mutations reported in
our previous studies, we have now identified 177 mutations in these 262
LQTS individuals (68%). The failure to identify mutations in 32% of
the individuals may result from phenotypic errors, incomplete
sensitivity of SSCP, or presence of mutations in regulatory sequences.
However, it is also clear that additional LQTS genes await
discovery.7 8
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Missense mutations were most common (72%), followed by
frameshift mutations (10%), in-frame deletions, and nonsense and
splice-site mutations (5% to 7% each, Table 7). Most mutations
resided in intracellular (52%) and transmembrane (30%) domains; 12%
were found in pore and 6% in extracellular segments (Table 8). One hundred one of the 129 distinct
LQTS mutations (78%) were identified in single families or
individuals. Most of the 177 mutations were found in KVLQT1
(n=75; 42%) and HERG (n=80; 45%). These 2 genes accounted
for 87% of the identified mutations, and mutations in SCN5A
(n=14; 8%), KCNE1 (n=5; 3%), and KCNE2 (n=3;
2%) accounted for the other 13%.
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Multiple mutations were found in regions encoding S5, S5/P, P, and S6 of KVLQT1 and HERG. The P region of potassium channels forms the outer pore and contains the selectivity filter.70 Transmembrane segment 6, corresponding to the inner helix of KcsA, forms the inner two thirds of the pore. This structure is supported by the S5 transmembrane segment, corresponding to the outer helix of KcsA, and is conserved from prokaryotes to eukaryotes.71 Mutations in these regions will most likely disrupt potassium transport. Many mutations were identified in the C-termini of KVLQT1 and HERG. Changes in the C-terminus of HERG could lead to anomalies in tetramerization, because it has been proposed that the C-terminus of eag, which is related to HERG, is involved in this process.72
Multiple mutations were also identified in regions that were different for KVLQT1 and HERG. In KVLQT1, multiple mutations were found in the sequences coding for the S2/S3 and S4/S5 linkers. Coexpression of S2/S3 mutants with wild-type KVLQT1 in Xenopus oocytes led to simple loss of function or dominant-negative effect without significantly changing the biophysical properties of IKs channels.16 17 73 Conversely, S4/S5 mutations altered the gating properties of the channels and modified KVLQT1 interactions with minK subunits.73 74 In HERG, more than 20 mutations were identified in the N-terminus. HERG channels lacking this region deactivate faster, and mutations in the region had a similar effect.75
Mutations in KCNE1 and KCNE2, encoding minK
and MiRP1, the respective IKs and
IKr ß-subunits, altered the biophysical
properties of the channels.12 13 76 An MiRP1 mutant
involved in clarithromycin-induced arrhythmia increased channel
blockade by the antibiotic.13 Mutations in
SCN5A, the sodium channel -subunit responsible for
cardiac INa, destabilized the inactivation
gate, causing delayed channel inactivation and dispersed
reopenings.21 22 59 77 One SCN5A mutant affected the
interactions with the sodium channel ß-subunit.54
It is interesting to note that probands with KCNE1 and KCNE2 mutations were older and had shorter QTc than probands with the other genotypes. The significance of these differences is unknown, however, because the number of probands with KCNE1 and KCNE2 genotypes was small.
This catalogue of mutations will facilitate genotype-phenotype analyses. It also has clinical implications for presymptomatic diagnosis and, in some cases, for therapy. Patients with mutations in KVLQT1, HERG, KCNE1, and KCNE2, for example, may benefit from potassium therapy.78 Conversely, sodium channel blockers might be helpful in patients with SCN5A mutations.79 The identification of mutations is of importance for ion channel studies as well. The expression of mutant channels in heterologous systems can reveal how structural changes influence the behavior of the channel or how mutations affect processing.80 81 These studies improve our understanding of channel function and provide insights into mechanisms of disease. Finally, mutation identification will contribute to the development of genetic screening for arrhythmia susceptibility.
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Acknowledgments |
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This work was supported by the National Heart, Lung, and Blood Institute (grants RO1-HL-46401, RO1-HL-33843, RO1-HL-51618, P50-HL-52338, and MO1-RR-000064) and by an award from Bristol-Myers Squibb. We are indebted to the family members for their participation. We wish to thank the SADS foundation and Dr Wojczech Zareba. We also wish to thank all centers and physicians that contributed invaluable phenotypic data and samples.
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Footnotes |
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1 References 9–13, 16, 18, 23, 25–27, 29, 30 and 32–69.
Guest Editor for this article was Christine Seidman, MD, Harvard Medical School, Boston, Mass.
The References for this article can be found Online at www.circulationaha.org
Received July 7, 1999; revision received April 3, 2000; accepted April 6, 2000.
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A. J. Wilson, K. V. Quinn, F. M. Graves, M. Bitner-Glindzicz, and A. Tinker Abnormal KCNQ1 trafficking influences disease pathogenesis in hereditary long QT syndromes (LQT1) Cardiovasc Res, August 15, 2005; 67(3): 476 - 486. [Abstract] [Full Text] [PDF]
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D. Thomas, A.-B. Wimmer, C. A. Karle, M. Licka, M. Alter, M. Khalil, H. E. Ulmer, S. Kathofer, J. Kiehn, H. A. Katus, et al. Dominant-negative IKs suppression by KCNQ1-{Delta}F339 potassium channels linked to Romano-Ward syndrome Cardiovasc Res, August 15, 2005; 67(3): 487 - 497. [Abstract] [Full Text] [PDF]
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J.M. Cordeiro, R. Brugada, Y.S. Wu, K. Hong, and R. Dumaine Modulation of IKr inactivation by mutation N588K in KCNH2: A link to arrhythmogenesis in short QT syndrome Cardiovasc Res, August 15, 2005; 67(3): 498 - 509. [Abstract] [Full Text] [PDF]
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J R Skinner, S-K Chung, D Montgomery, C H McCulley, J Crawford, J French, and M I Rees Near-miss SIDS due to Brugada syndrome Arch. Dis. Child., May 1, 2005; 90(5): 528 - 529. [Abstract] [Full Text] [PDF]
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L. Nie, W. Feng, R. Diaz, M. A. Gratton, K. J. Doyle, and E. N. Yamoah Functional Consequences of Polyamine Synthesis Inhibition by L-{alpha}-Difluoromethylornithine (DFMO): CELLULAR MECHANISMS FOR DFMO-MEDIATED OTOTOXICITY J. Biol. Chem., April 15, 2005; 280(15): 15097 - 15102. [Abstract] [Full Text] [PDF]
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A. J. Moss and P. J. Schwartz 25th Anniversary of the International Long-QT Syndrome Registry: An Ongoing Quest to Uncover the Secrets of Long-QT Syndrome Circulation, March 8, 2005; 111(9): 1199 - 1201. [Full Text] [PDF]
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T. M. Olson, V. V. Michels, J. D. Ballew, S. P. Reyna, M. L. Karst, K. J. Herron, S. C. Horton, R. J. Rodeheffer, and J. L. Anderson Sodium Channel Mutations and Susceptibility to Heart Failure and Atrial Fibrillation JAMA, January 26, 2005; 293(4): 447 - 454. [Abstract] [Full Text] [PDF]
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C. E. Clancy and R. S. Kass Inherited and Acquired Vulnerability to Ventricular Arrhythmias: Cardiac Na+ and K+ Channels Physiol Rev, January 1, 2005; 85(1): 33 - 47. [Abstract] [Full Text] [PDF]
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S. D. Gage and W. R. Kobertz KCNE3 Truncation Mutants Reveal a Bipartite Modulation of KCNQ1 K+ Channels J. Gen. Physiol., November 29, 2004; 124(6): 759 - 771. [Abstract] [Full Text] [PDF]
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X. H. T. Wehrens and A. R. Marks Sudden Unexplained Death Caused by Cardiac Ryanodine Receptor (RyR2) Mutations Mayo Clin. Proc., November 1, 2004; 79(11): 1367 - 1371. [PDF]
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L. Zhang, G. M. Vincent, M. Baralle, F. E. Baralle, B. D. Anson, D. W. Benson, B. Whiting, K. W. Timothy, J. Carlquist, C. T. January, et al. An intronic mutation causes long QT syndrome J. Am. Coll. Cardiol., September 15, 2004; 44(6): 1283 - 1291. [Abstract] [Full Text] [PDF]
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 T. Jespersen, H. B. Rasmussen, M. Grunnet, H. S. Jensen, K. Angelo, D. S. Dupuis, L. K. Vogel, N. K. Jorgensen, D. A. Klaerke, and S.-P. Olesen Basolateral localisation of KCNQ1 potassium channels in MDCK cells: molecular identification of an N-terminal targeting motif J. Cell Sci., September 1, 2004; 117(19): 4517 - 4526. [Abstract] [Full Text] [PDF]
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H. Kanki, S. Kupershmidt, T. Yang, S. Wells, and D. M. Roden A Structural Requirement for Processing the Cardiac K+ Channel KCNQ1 J. Biol. Chem., August 6, 2004; 279(32): 33976 - 33983. [Abstract] [Full Text] [PDF]
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E. Villain, I. Denjoy, J.M. Lupoglazoff, P. Guicheney, B. Hainque, V. Lucet, and D. Bonnet Low incidence of cardiac events with {beta}-blocking therapy in children with long QT syndrome Eur. Heart J., August 2, 2004; 25(16): 1405 - 1411. [Abstract] [Full Text] [PDF]
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Q. Gong, C. L. Anderson, C. T. January, and Z. Zhou Pharmacological rescue of trafficking defective HERG channels formed by coassembly of wild-type and long QT mutant N470D subunits Am J Physiol Heart Circ Physiol, August 1, 2004; 287(2): H652 - H658. [Abstract] [Full Text] [PDF]
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W. Shimizu, M. Horie, S. Ohno, K. Takenaka, M. Yamaguchi, M. Shimizu, T. Washizuka, Y. Aizawa, K. Nakamura, T. Ohe, et al. Mutation site-specific differences in arrhythmic risk and sensitivity to sympathetic stimulation in the LQT1 form of congenital long QT syndrome: Multicenter study in Japan J. Am. Coll. Cardiol., July 7, 2004; 44(1): 117 - 125. [Abstract] [Full Text] [PDF]
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L. Gouas, C. Bellocq, M. Berthet, F. Potet, S. Demolombe, A. Forhan, R. Lescasse, F. Simon, B. Balkau, I. Denjoy, et al. New KCNQ1 mutations leading to haploinsufficiency in a general population: Defective trafficking of a KvLQT1 mutant Cardiovasc Res, July 1, 2004; 63(1): 60 - 68. [Abstract] [Full Text] [PDF]
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