(Circulation. 1997;96:2778-2781.)
© 1997 American Heart Association, Inc.
Articles |
KVLQT1 C-Terminal Missense Mutation Causes a Forme Fruste Long-QT Syndrome
From INSERM U153, Groupe Hospitalier Pitié-Salpêtrière, Institut de Myologie, Paris (C.D., M.B., N.N., M.B., K.S., P.G.) and Service de Cardiologie, Hôpital Lariboisière (I.D., N.N., P.C.) Paris; Château des Côtes, Les Loges en Josas (I.D.); Généthon-CNRS URA 1922, Evry (C.C.); and Service de Cardiologie, Hôpital de Brabois, Nancy (G.C.), France.
Correspondence to Pascale Guicheney, INSERM U153, Institut de Myologie, Groupe Hospitalier Pitié-Salpêtrière, 47 blvd de l'Hôpital, 75651 Paris Cedex 13, France. E-mail pguichen{at}myologie.infobiogen.fr
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Abstract |
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Background KVLQT1, the gene encoding the
-subunit of a cardiac potassium channel, is the most common cause of
the dominant form of long-QT syndrome (LQT1-type), the Romano-Ward
syndrome (RWS). The overall phenotype of RWS is characterized
by a prolonged QT interval on the ECG and cardiac
ventricular arrhythmias leading to recurrent
syncopes and sudden death. However, there is considerable variability
in the clinical presentation, and potential severity is
often difficult to evaluate. To analyze the relationship
between phenotypes and underlying defects in
KVLQT1, we investigated mutations in this gene in 20 RWS
families originating from France. Methods and Results By PCR-SSCP analysis, 16 missense mutations were identified in KVLQT1, 11 of them being novel. Fifteen mutations, localized in the transmembrane domains S2-S3, S4-S5, P, and S6, were associated with a high percentage of symptomatic carriers (55 of 95, or 58%) and sudden deaths (23 of 95, or 24%). In contrast, a missense mutation, Arg555Cys, identified in the C-terminal domain in 3 families, was associated with a significantly less pronounced QT prolongation (459±33 ms, n=41, versus 480±32 ms, n=70, P=.0012), and significantly lower percentages of symptomatic carriers (7 of 44, or 16%, P<.001) and sudden deaths (2 of 44, or 5%, P<.01). Most of the cardiac events occurring in these 3 families were triggered by drugs known to affect ventricular repolarization.
Conclusions Our data show a wide KVLQT1 allelic heterogeneity among 20 families in which KVLQT1 causes RWS. We describe the first missense mutation in the C-terminal domain of KVLQT1, which is clearly associated with a fruste phenotype, which could be a favoring factor of acquired LQT syndrome.
Key Words: antiarrhythmia agents • tachyarrhythmias • heart defects, congenital • death, sudden
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Introduction |
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Genetic studies have shown that the autosomal dominant form of LQTS, the RWS, is a genetically heterogenous disease caused by mutations in at least four genes (LQT1 to LQT4).1 Three of them have been identified and encode ion channel subunits: KVLQT1, a potassium channel that accounts for most of the RWS cases (LQT1 type on 11p15.5),2 HERG, the potassium channel that underlies IKr (LQT2 on 7q35-36), and SCN5A, the cardiac sodium channel (LQT3 on 3p21).1 KVLQT1 also causes the recessive form of LQTS, the JLNS.3,4 RWS and JLNS have in common an abnormal repolarization visualized as a prolonged QT interval on the surface ECG, recurrent syncopes, and risk of sudden death.5 In JLNS, homozygous carriers of a KVLQT1 mutation have, in addition, a congenital deafness, whereas the heterozygous carriers are generally asymptomatic.3
To increase our understanding of the phenotype/genotype relationship of patients with RWS, we have focused our analysis on KVLQT1 mutations. So far, 15 mutations localized in the transmembrane domains have been identified in families from the United States, South Africa, and Japan.2,6-8 In this study, we identified the mutations causing RWS in 20 families originating from France, and we report the clinical data for each of them. A novel mutation in the C-terminal domain, identified in 3 families, was clearly associated with a mild clinical presentation and worsened under ventricular repolarization prolonging drugs.
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Methods |
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Subjects
Clinical evaluation and blood samples were obtained after written informed consent in accordance with the guidelines set down by the Comité Consultatif de Protection des Personnes dans la Recherche Biomédicale du Groupe Hospitalier de la Pitié-Salpêtrière (Paris). Subjects underwent detailed clinical and cardiovascular examination, including a 12-lead ECG and 24-hour Holter monitoring. The QT intervals were measured on the ECG in lead II or V5 and corrected for heart rate (QTc, in ms) by use of the Bazett formula.9 Subjects were considered to be affected when they presented with (1) syncopes or documented torsades de pointes, (2) QTc>460 ms, or (3) QTc>440 ms associated with bradycardia or abnormal T-wave pattern.10 All families originated from France, even the 2 who were living in the United States (9364) and Reunion Island (2956).
SSCP Analysis and Direct Sequencing of PCR
Products
Primers designed by Wang et al2 were used
to amplify the KVLQT1 region between S2 and S6 transmembrane
segments from genomic DNA. The primer set (DL-DR) was previously
designed to amplify part of the KVLQT1 C-terminal domain
from genomic DNA.3 SSCP analysis and
sequencing of the PCR products were performed as described
elsewhere.3 For each abnormal SSCP pattern, the
cosegregation with the disease was studied in the family. All the
mutations were screened on 200 chromosomes from unrelated control
subjects.
Statistical Analysis
Data are given as mean±SD. Mean QTc
values were compared by unpaired Student's t test, with
P<.05 considered statistically significant, and percentages
by 
2 test.
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Results |
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By PCR-SSCP analysis, we identified 16 KVLQT1 missense mutations, which were absent in the control subjects (Table
). These mutations changed amino
acid residues, which are highly conserved throughout evolution, from
Caenorhabditis elegans to Homo
sapiens.11 Eleven of them were novel, and 5
have been reported previously.2,6-8 Mutations
were localized (1) in the P and S6 domains and in the S2-S3 and S4-S5
cytoplasmic loops, in agreement with the first report of Wang et
al,2 and (2) in the C-terminal region where we
previously identified the first JLN mutation, which was an
insertion-deletion mutation leading to a premature stop
codon.3
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Syncopes and documented sudden deaths were taken into account to
evaluate the frequency of symptoms for each mutation (Table
).
The highest frequency of cardiac events was detected among carriers of mutations in the transmembrane domains, especially in the S4-S5 loop (67%, 14/21), the P domain (66%, 23/35), and the S6 domain (54%, 13/24). For most of the cases, the first syncope was triggered by physical activity before age 10 years, and sudden deaths occurred in untreated patients with a history of recurrent syncopes.
The mean QTc value was determined for carriers of mutations located in the S2-S3 loop (476±25 ms, n=12), the S4-S5 loop (490±46 ms, n=11), the P domain (483±32 ms, n=27), and the S6 domain (472±27 ms, n=20). No significant difference was found between these subgroups. The mean QTc value for all the carriers of a mutation in the transmembrane domains was 480±32 ms (n=70).
In contrast to the mutations in the transmembrane domains, the
C-terminal mutation, Arg555Cys, which was
identified in 3 families, clearly caused a milder phenotype
(Figure, Table). Indeed, among the 44 carriers of the
Arg555Cys mutation, only 5 living subjects
experienced syncope, and 2 died suddenly (Figure). One of the sudden
deaths occurred in a 38-year-old woman treated with terfenadine (F8006,
II5). The other sudden death occurred in a 35-year-old woman with a
history of palpitation and dizziness. She also experienced two syncopes
at the age of 18 years at arousal while she was being treated for
tonsillitis (F1387, III11). Among the 5 other syncopal events in these
families, 3 occurred under disopyramide (F1387, III13),
meflaquine (F8006, II2), and diuretics (F1822,
III2), which are drugs known to modify ventricular
repolarization. It is noteworthy that no syncopal episode occurred
before the age of 10 in these families, in contrast to what was
observed for mutations in the transmembrane domains (Table). The
QTc intervals of the
Arg555Cys mutation carriers were often borderline
or even normal (<440 ms) (Figure) but were variable at follow-up.
The QTc values were significantly lower than in
the case of mutations in the transmembrane domains (459±33 ms, n=41
versus 480±32 ms, n=70; P=.0012), or in the S4-S5 loop
(490±46 ms, n=11, P=.014), or in the P domain (483±32 ms,
n=27, P=.0035).
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Discussion |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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This is the first report of a missense mutation located in the C-terminal region of KVLQT1 in RWS families. Numerous missense mutations in voltage-gated ionic channels have previously been reported in human diseases in addition to LQTS. Hyperkalemic periodic paralysis, paramyotonia congenita, and sodium channel myotonia are skeletal muscle sodium channel disorders (SCN4A), hypokalemic paralysis is caused by mutations in the voltage-gated calcium channel (CACNL1A3), and episodic ataxia is caused by mutations in a neuronal voltage-gated potassium channel (KCNA1).12-14 It is noteworthy that no missense mutations in the C-terminal domains of these various channels have been described so far. An important feature is that the mutation Arg555Cys is associated with a less severe phenotype than the mutations previously or currently reported occurring in the transmembrane regions of the
-subunit. Indeed, the
percentage of syncopes and sudden deaths among the carriers of the
C-terminal mutation is significantly lower compared with the carriers
of the other mutations (16% versus 58%, P<.001). In
addition, the occurrence of sudden deaths is significantly lower (5%
versus 24%, P<.01). The most severe phenotypes
were associated with transmembrane domain mutations located in the P
domain and the S4-S5 loop. Nevertheless, the phenotype of the
S2-S3 loop mutations seems less severe and could represent
intermediate forms between typical and fruste forms of LQTS. These
observations need to be verified in larger series. The phenotypic differences between the Arg555Cys mutation and the other mutations are in agreement with our recent in vitro data,11 in which mutated proteins have been produced and expressed in COS cells, in the presence of IsK as described in References 15 and 1615 16 . The mutated Arg555Cys subunit formed a functional channel, although it exhibited abnormal gating properties: the voltage dependence of the activation was strongly shifted to more positive values, and deactivation kinetics were accelerated. In contrast, all other mutated subunits formed nonfunctional channels in the homozygous state.
Carriers of the Arg555Cys mutation have a minor or no QTc prolongation and are generally devoid of emotion or exercise-induced syncopes, in particular in the first decade of life, but may experience drug-induced major QTc prolongation and arrhythmias. The current standard LQT diagnostic criteria17 did not allow diagnosis of such patients. We thus used a lower cutoff value of 440 ms, but associated with two other important ECG parameters, bradycardia or abnormal T-wave pattern.10 Detection of gene carriers is clinically relevant, because severe symptoms and sudden death can be triggered in these patients by drugs known to induce ventricular repolarization prolongation.18-20 In conclusion, a follow-up of clearly identified RW mutation carriers and a better knowledge of the phenotype associated with each mutation are essential for proper patient management and counseling.
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Selected Abbreviations and Acronyms |
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440 ms and
QTc<440 ms, respectively, as determined on first available
ECG. S denotes symptomatic individuals. |
Acknowledgments |
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This work was supported by the Institut National de la Santé et de la Recherche Médicale (Clinical Research Network No. 494012), the Association Française contre les Myopathies, the Direction de la Recherche Clinique des Hôpitaux de Paris (PHRC P-920308), and the European Community (BMH4-CT96-0028). We are indebted to the family members, without whose participation this work could not have been done. We thank Dr L. Bailly, Dr M. Cavailles, Dr P. Chavernac, Dr P. Chevalier, Dr P. Cosnay, Dr J.C. Daubert, Dr J.M. Davy, Dr J.P. Favier, Dr F. Heitz, Dr M. Komajda, Dr D. Lamaison, Dr A. Leenhardt, Dr V. Lucet, Dr J. Poinsot, and Dr J. Victor for their participation in clinical examinations and Dr J. Barhanin for helpful discussion.
Received June 26, 1997; revision received August 8, 1997; accepted August 12, 1997.
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D. M. Roden Pharmacogenetics and drug-induced arrhythmias Cardiovasc Res, May 1, 2001; 50(2): 224 - 231. [Abstract] [Full Text] [PDF]
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P. Chevalier, C. Rodriguez, L. Bontemps, M. Miquel, G. Kirkorian, R. Rousson, F. Potet, J.-J. Schott, I. Baro, and P. Touboul Non-invasive testing of acquired long QT syndrome: Evidence for multiple arrhythmogenic substrates Cardiovasc Res, May 1, 2001; 50(2): 386 - 398. [Abstract] [Full Text] [PDF]
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J. M. Lupoglazoff, I. Denjoy, M. Berthet, N. Neyroud, L. Demay, P. Richard, B. Hainque, G. Vaksmann, D. Klug, A. Leenhardt, et al. Notched T Waves on Holter Recordings Enhance Detection of Patients With LQT2 (HERG) Mutations Circulation, February 27, 2001; 103(8): 1095 - 1101. [Abstract] [Full Text] [PDF]
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K. Piippo, H. Swan, M. Pasternack, H. Chapman, K. Paavonen, M. Viitasalo, L. Toivonen, and K. Kontula A founder mutation of the potassium channel KCNQ1 in long QT syndrome: Implications for estimation of disease prevalence and molecular diagnostics J. Am. Coll. Cardiol., February 1, 2001; 37(2): 562 - 568. [Abstract] [Full Text] [PDF]
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L. Bianchi, S. G. Priori, C. Napolitano, K. A. Surewicz, A. T. Dennis, M. Memmi, P. J. Schwartz, and A. M. Brown Mechanisms of IKs suppression in LQT1 mutants Am J Physiol Heart Circ Physiol, December 1, 2000; 279(6): H3003 - H3011. [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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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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P. G.A. Volders, M. A. Vos, B. Szabo, K. R. Sipido, S.H.M. de Groot, A. P.M. Gorgels, H. J.J. Wellens, and R. Lazzara Progress in the understanding of cardiac early afterdepolarizations and torsades de pointes: time to revise current concepts Cardiovasc Res, June 1, 2000; 46(3): 376 - 392. [Full Text] [PDF]
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C. Chouabe, N. Neyroud, P. Richard, I. Denjoy, B. Hainque, G. Romey, M.-D. Drici, P. Guicheney, and J. Barhanin Novel mutations in KvLQT1 that affect Iks activation through interactions with Isk Cardiovasc Res, March 1, 2000; 45(4): 971 - 980. [Abstract] [Full Text] [PDF]
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F. Lehmann-Horn and K. Jurkat-Rott Voltage-Gated Ion Channels and Hereditary Disease Physiol Rev, October 1, 1999; 79(4): 1317 - 1372. [Abstract] [Full Text] [PDF]
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A. Murray, C. Donger, C. Fenske, I. Spillman, P. Richard, Y. B. Dong, N. Neyroud, P. Chevalier, I. Denjoy, N. Carter, et al. Splicing Mutations in KCNQ1 : A Mutation Hot Spot at Codon 344 That Produces In Frame Transcripts Circulation, September 7, 1999; 100(10): 1077 - 1084. [Abstract] [Full Text] [PDF]
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H. Swan, M. Viitasalo, K. Piippo, P.a. Laitinen, K. Kontula, and L. Toivonen Sinus node function and ventricular repolarization during exercise stress test in long QT syndrome patients with KvLQT1 and HERG potassium channel defects J. Am. Coll. Cardiol., September 1, 1999; 34(3): 823 - 829. [Abstract] [Full Text] [PDF]
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A. M. J. Choy, D. Darbar, S. Dell'Orto, and D. M. Roden Exaggerated QT prolongation after cardioversion of atrial fibrillation J. Am. Coll. Cardiol., August 1, 1999; 34(2): 396 - 401. [Abstract] [Full Text] [PDF]
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L. Franqueza, M. Lin, I. Splawski, M. T. Keating, and M. C. Sanguinetti Long QT Syndrome-associated Mutations in the S4-S5 Linker of KvLQT1 Potassium Channels Modify Gating and Interaction with minK Subunits J. Biol. Chem., July 23, 1999; 274(30): 21063 - 21070. [Abstract] [Full Text] [PDF]
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M. Berthet, I. Denjoy, C. Donger, L. Demay, H. Hammoude, D. Klug, E. Schulze-Bahr, P. Richard, H. Funke, K. Schwartz, et al. C-terminal HERG Mutations : The Role of Hypokalemia and a KCNQ1-Associated Mutation in Cardiac Event Occurrence Circulation, March 23, 1999; 99(11): 1464 - 1470. [Abstract] [Full Text] [PDF]
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Q. Chen, D. Zhang, R. L. Gingell, A. J. Moss, C. Napolitano, S. G. Priori, P. J. Schwartz, E. Kehoe, J. L. Robinson, E. Schulze-Bahr, et al. Homozygous Deletion in KVLQT1 Associated With Jervell and Lange-Nielsen Syndrome Circulation, March 16, 1999; 99(10): 1344 - 1347. [Abstract] [Full Text] [PDF]
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N. Neyroud, P. Richard, N. Vignier, C. Donger, I. Denjoy, L. Demay, M. Shkolnikova, R. Pesce, P. Chevalier, B. Hainque, et al. Genomic Organization of the KCNQ1 K+ Channel Gene and Identification of C-Terminal Mutations in the Long-QT Syndrome Circ. Res., February 19, 1999; 84(3): 290 - 297. [Abstract] [Full Text] [PDF]
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S. G. Priori, J. Barhanin, R. N. W. Hauer, W. Haverkamp, H. J. Jongsma, A. G. Kleber, W. J. McKenna, D. M. Roden, Y. Rudy, K. Schwartz, et al. Genetic and Molecular Basis of Cardiac Arrhythmias: Impact on Clinical Management Parts I and II Circulation, February 2, 1999; 99(4): 518 - 528. [Abstract] [Full Text] [PDF]
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S. G. Priori, C. Napolitano, and P. J. Schwartz Low Penetrance in the Long-QT Syndrome : Clinical Impact Circulation, February 2, 1999; 99(4): 529 - 533. [Abstract] [Full Text] [PDF]
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S.G. Priori, J. Barhanin, R.N.W. Hauer, W. Haverkamp, H.J. Jongsma, A.G. Kleber, W.J. McKenna, D.M. Roden, Y. Rudy, K. Schwartz, et al. Genetic and molecular basis of cardiac arrhythmias: Impact on clinical management Eur. Heart J., February 1, 1999; 20(3): 174 - 195. [PDF]
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M.-D. Drici, I. Arrighi, C. Chouabe, J. R. Mann, M. Lazdunski, G. Romey, and J. Barhanin Involvement of IsK-Associated K+ Channel in Heart Rate Control of Repolarization in a Murine Engineered Model of Jervell and Lange-Nielsen Syndrome Circ. Res., July 13, 1998; 83(1): 95 - 102. [Abstract] [Full Text] [PDF]
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F. Sesti, G. W. Abbott, J. Wei, K. T. Murray, S. Saksena, P. J. Schwartz, S. G. Priori, D. M. Roden, A. L. George Jr., and S. A. N. Goldstein A common polymorphism associated with antibiotic-induced cardiac arrhythmia PNAS, September 12, 2000; 97(19): 10613 - 10618. [Abstract] [Full Text] [PDF]
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P. Yang, H. Kanki, B. Drolet, T. Yang, J. Wei, P. C. Viswanathan, S. H. Hohnloser, W. Shimizu, P. J. Schwartz, M. Stanton, et al. Allelic Variants in Long-QT Disease Genes in Patients With Drug-Associated Torsades de Pointes Circulation, April 23, 2002; 105(16): 1943 - 1948. [Abstract] [Full Text] [PDF]
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