This Article Full Text Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Shalaby, F. Y. Articles by Blanar, M. A. Search for Related Content PubMed PubMed Citation Articles by Shalaby, F. Y. Articles by Blanar, M. A.

(Circulation. 1997;96:1733-1736.)
© 1997 American Heart Association, Inc.

Articles

Dominant-Negative KvLQT1 Mutations Underlie the LQT1 Form of Long QT Syndrome

Fouad Y. Shalaby, PhD; Paul C. Levesque, PhD; Wen-Pin Yang, PhD; Wayne A. Little, MS; Mary Lee Conder, BS; Tonya Jenkins-West, BS; ; Michael A. Blanar, PhD

From the Department of Cardiovascular Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ.

Correspondence to Dr Michael A. Blanar, Department of Cardiovascular Drug Discovery, Mail Code K14-01, Room K.4125A, Bristol-Myers Squibb Pharmaceutical Research Institute, Route 206 and Provinceline Road, Princeton, NJ 08543-4000. E-mail blanar{at}bms.com

Background Mutations that map to the KvLQT1 gene on human chromosome 11 account for more than 50% of inherited long QT syndrome (LQTS). It has been discovered recently that the KvLQT1 and minK proteins functionally interact to generate a current with biophysical properties similar to I_Ks, the slowly activating delayed-rectifier cardiac potassium current. Since I_Ks modulates the repolarization of cardiac action potentials it is reasonable to hypothesize that mutations in KvLQT1 reduce I_Ks, resulting in the prolongation of cardiac action potential duration.

Methods and Results We expressed LQTS-associated KvLQT1 mutants in Xenopus oocytes either individually or in combination with wild-type KvLQT1 or in combination with both wild-type KvLQT1 and minK. Substitutions of alanine with proline in the S2-S3 cytoplasmic loop (A177P) or threonine with isoleucine in the highly conserved signature sequence of the pore (T311I) yield inactive channels when expressed individually, whereas substitution of leucine with phenylalanine in the S5 transmembrane domain (L272F) yields a functional channel with reduced macroscopic conductance. However, all these mutants inhibit wild-type KvLQT1 currents in a dominant-negative fashion.

Conclusions In LQTS-affected individuals these mutations would be predicted to result in a diminution of the cardiac I_Ks current, subsequent prolongation of cardiac repolarization, and an increased risk of arrhythmias.

Key Words: arrhythmia • potassium channels • long QT syndrome

This article has been cited by other articles:

				G. Gibor, D. Yakubovich, A. Rosenhouse-Dantsker, A. Peretz, H. Schottelndreier, G. Seebohm, N. Dascal, D. E. Logothetis, Y. Paas, and B. Attali An Inactivation Gate in the Selectivity Filter of KCNQ1 Potassium Channels Biophys. J., December 15, 2007; 93(12): 4159 - 4172. [Abstract] [Full Text] [PDF]

				S. E. Lehnart, M. J. Ackerman, D. W. Benson Jr, R. Brugada, C. E. Clancy, J. K. Donahue, A. L. George Jr, A. O. Grant, S. C. Groft, C. T. January, et al. Inherited Arrhythmias: A National Heart, Lung, and Blood Institute and Office of Rare Diseases Workshop Consensus Report About the Diagnosis, Phenotyping, Molecular Mechanisms, and Therapeutic Approaches for Primary Cardiomyopathies of Gene Mutations Affecting Ion Channel Function Circulation, November 13, 2007; 116(20): 2325 - 2345. [Abstract] [Full Text] [PDF]

				A. J. Moss, W. Shimizu, A. A.M. Wilde, J. A. Towbin, W. Zareba, J. L. Robinson, M. Qi, G. M. Vincent, M. J. Ackerman, E. S. Kaufman, et al. Clinical Aspects of Type-1 Long-QT Syndrome by Location, Coding Type, and Biophysical Function of Mutations Involving the KCNQ1 Gene Circulation, May 15, 2007; 115(19): 2481 - 2489. [Abstract] [Full Text] [PDF]

				I. R. Boulet, A. L. Raes, N. Ottschytsch, and D. J. Snyders Functional effects of a KCNQ1 mutation associated with the long QT syndrome Cardiovasc Res, June 1, 2006; 70(3): 466 - 474. [Abstract] [Full Text] [PDF]

				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]

				K.-H. Park, J. Piron, S. Dahimene, J. Merot, I. Baro, D. Escande, and G. Loussouarn Impaired KCNQ1-KCNE1 and Phosphatidylinositol-4,5-Bisphosphate Interaction Underlies the Long QT Syndrome Circ. Res., April 15, 2005; 96(7): 730 - 739. [Abstract] [Full Text] [PDF]

				G. Seebohm, P. Westenskow, F. Lang, and M. C Sanguinetti Mutation of colocalized residues of the pore helix and transmembrane segments S5 and S6 disrupt deactivation and modify inactivation of KCNQ1 K+ channels J. Physiol., March 1, 2005; 563(2): 359 - 368. [Abstract] [Full Text] [PDF]

				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]

				M.R. K. Bhagavatula, C. Fan, G.-Q. Shen, J. Cassano, E. F. Plow, E. J. Topol, and Q. Wang Transcription factor MEF2A mutations in patients with coronary artery disease Hum. Mol. Genet., December 15, 2004; 13(24): 3181 - 3188. [Abstract] [Full Text] [PDF]

				L. Wu, J. C. Shryock, Y. Song, Y. Li, C. Antzelevitch, and L. Belardinelli Antiarrhythmic Effects of Ranolazine in a Guinea Pig in Vitro Model of Long-QT Syndrome J. Pharmacol. Exp. Ther., August 1, 2004; 310(2): 599 - 605. [Abstract] [Full Text] [PDF]

				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]

				I. D. Millar, J. A. Hartley, C. Haigh, A. A. Grace, S. J. White, J. D. Kibble, and L. Robson Volume regulation is defective in renal proximal tubule cells isolated from KCNE1 knockout mice Exp Physiol, March 1, 2004; 89(2): 173 - 180. [Abstract] [Full Text] [PDF]

				G. Seebohm, M. Pusch, J. Chen, and M. C. Sanguinetti Pharmacological Activation of Normal and Arrhythmia-Associated Mutant KCNQ1 Potassium Channels Circ. Res., November 14, 2003; 93(10): 941 - 947. [Abstract] [Full Text] [PDF]

				N. Gamper, J. D. Stockand, and M. S. Shapiro Subunit-Specific Modulation of KCNQ Potassium Channels by Src Tyrosine Kinase J. Neurosci., January 1, 2003; 23(1): 84 - 95. [Abstract] [Full Text] [PDF]

				A. A.M. Wilde and D. Escande LQT genotype-phenotype relationships: patients and patches Cardiovasc Res, September 1, 2001; 51(4): 627 - 629. [Full Text] [PDF]

				C.-C. Shieh, M. Coghlan, J. P. Sullivan, and M. Gopalakrishnan Potassium Channels: Molecular Defects, Diseases, and Therapeutic Opportunities Pharmacol. Rev., December 1, 2000; 52(4): 557 - 594. [Abstract] [Full Text] [PDF]

				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]

				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]

				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]

				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]

				D. Weinshenker, A. Wei, L. Salkoff, and J. H. Thomas Block of an ether-a-go-go-Like K+ Channel by Imipramine Rescues egl-2 Excitation Defects in Caenorhabditis elegans J. Neurosci., November 15, 1999; 19(22): 9831 - 9840. [Abstract] [Full Text] [PDF]

				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]

				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]

				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]

				W.-P. Yang, P. C. Levesque, W. A. Little, M. L. Conder, P. Ramakrishnan, M. G. Neubauer, and M. A. Blanar Functional Expression of Two KvLQT1-related Potassium Channels Responsible for an Inherited Idiopathic Epilepsy J. Biol. Chem., July 31, 1998; 273(31): 19419 - 19423. [Abstract] [Full Text] [PDF]

				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]

				G. Seebohm, C. R. Scherer, A. E. Busch, and C. Lerche Identification of Specific Pore Residues Mediating KCNQ1 Inactivation. A NOVEL MECHANISM FOR LONG QT SYNDROME J. Biol. Chem., April 20, 2001; 276(17): 13600 - 13605. [Abstract] [Full Text] [PDF]