New mutations in the KVLQT1 potassium channel that cause long-QT syndrome

Hua Li, Qiuyun Chen, Arthur J. Moss, Jennifer Robinson, Veronica Goytia, James C. Perry, G. Michael Vincent, Silvia G. Priori, Michael H. Lehmann, Susan W. Denfield, Desmond Duff, Stephen Kaine, Wataru Shimizu, Peter J. Schwartz, Qing Wang, Jeffrey Towbin

Research output: Contribution to journalArticle

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Abstract

Background: Long-QT syndrome (LQTS) is an inherited cardiac arrhythmia that causes sudden death in young, otherwise healthy people. Four genes for LQTS have been mapped to chromosome 11p15.5 (LQT1), 7q35-36 (LQ72), 3p21-24 (LQT3), and 4q25-27 (LQT4). Genes responsible for LQT1, LQT2, and LQT3 have been identified as cardiac potassium channel genes (KVLQT1, HERG) and the cardiac sodium channel gene (SCN5A). Methods and Results: After studying 115 families with LQTS, we used single-strand conformation polymorphism (SSCP) and DNA sequence analysis to identify mutations in the cardiac potassium channel gene, KVLQT1. Affected members of seven LQTS families were found to have new, previously unidentified mutations, including two identical missense mutations, four identical splicing mutations, and one 3-bp deletion. An identical splicing mutation was identified in affected members of four unrelated families (one Italian, one Irish, and two American), leading to an alternatively spliced form of KVLQT1. The 3-bp deletion arose de novo and occurs at an exon-intron boundary. This results in a single base deletion in the KVLQT1 cDNA sequence and alters splicing, leading to the truncation of KVLQT1 protein. Conclusions: We have identified LQTS-causing mutations of KVLQT1 in seven families. Five KVLQT1 mutations cause the truncation of KVLQT1 protein. These data further confirm that KVLQT1 mutations cause LQTS. The location and character of these mutations expand the types of mutation, confirm a mutational hot spot, and suggest that they act through a loss-of- function mechanism or a dominant-negative mechanism.

Original languageEnglish (US)
Pages (from-to)1264-1269
Number of pages6
JournalCirculation
Volume97
Issue number13
DOIs
StatePublished - Apr 7 1998

Fingerprint

Long QT Syndrome
Potassium Channels
Mutation
KCNQ1 Potassium Channel
Genes
Sodium Channels
Missense Mutation
Sudden Death
DNA Sequence Analysis
Introns
Cardiac Arrhythmias
Cause of Death
Exons
Complementary DNA
Chromosomes

All Science Journal Classification (ASJC) codes

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

Cite this

Li, H., Chen, Q., Moss, A. J., Robinson, J., Goytia, V., Perry, J. C., ... Towbin, J. (1998). New mutations in the KVLQT1 potassium channel that cause long-QT syndrome. Circulation, 97(13), 1264-1269. https://doi.org/10.1161/01.CIR.97.13.1264

New mutations in the KVLQT1 potassium channel that cause long-QT syndrome. / Li, Hua; Chen, Qiuyun; Moss, Arthur J.; Robinson, Jennifer; Goytia, Veronica; Perry, James C.; Michael Vincent, G.; Priori, Silvia G.; Lehmann, Michael H.; Denfield, Susan W.; Duff, Desmond; Kaine, Stephen; Shimizu, Wataru; Schwartz, Peter J.; Wang, Qing; Towbin, Jeffrey.

In: Circulation, Vol. 97, No. 13, 07.04.1998, p. 1264-1269.

Research output: Contribution to journalArticle

Li, H, Chen, Q, Moss, AJ, Robinson, J, Goytia, V, Perry, JC, Michael Vincent, G, Priori, SG, Lehmann, MH, Denfield, SW, Duff, D, Kaine, S, Shimizu, W, Schwartz, PJ, Wang, Q & Towbin, J 1998, 'New mutations in the KVLQT1 potassium channel that cause long-QT syndrome', Circulation, vol. 97, no. 13, pp. 1264-1269. https://doi.org/10.1161/01.CIR.97.13.1264
Li H, Chen Q, Moss AJ, Robinson J, Goytia V, Perry JC et al. New mutations in the KVLQT1 potassium channel that cause long-QT syndrome. Circulation. 1998 Apr 7;97(13):1264-1269. https://doi.org/10.1161/01.CIR.97.13.1264
Li, Hua ; Chen, Qiuyun ; Moss, Arthur J. ; Robinson, Jennifer ; Goytia, Veronica ; Perry, James C. ; Michael Vincent, G. ; Priori, Silvia G. ; Lehmann, Michael H. ; Denfield, Susan W. ; Duff, Desmond ; Kaine, Stephen ; Shimizu, Wataru ; Schwartz, Peter J. ; Wang, Qing ; Towbin, Jeffrey. / New mutations in the KVLQT1 potassium channel that cause long-QT syndrome. In: Circulation. 1998 ; Vol. 97, No. 13. pp. 1264-1269.
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abstract = "Background: Long-QT syndrome (LQTS) is an inherited cardiac arrhythmia that causes sudden death in young, otherwise healthy people. Four genes for LQTS have been mapped to chromosome 11p15.5 (LQT1), 7q35-36 (LQ72), 3p21-24 (LQT3), and 4q25-27 (LQT4). Genes responsible for LQT1, LQT2, and LQT3 have been identified as cardiac potassium channel genes (KVLQT1, HERG) and the cardiac sodium channel gene (SCN5A). Methods and Results: After studying 115 families with LQTS, we used single-strand conformation polymorphism (SSCP) and DNA sequence analysis to identify mutations in the cardiac potassium channel gene, KVLQT1. Affected members of seven LQTS families were found to have new, previously unidentified mutations, including two identical missense mutations, four identical splicing mutations, and one 3-bp deletion. An identical splicing mutation was identified in affected members of four unrelated families (one Italian, one Irish, and two American), leading to an alternatively spliced form of KVLQT1. The 3-bp deletion arose de novo and occurs at an exon-intron boundary. This results in a single base deletion in the KVLQT1 cDNA sequence and alters splicing, leading to the truncation of KVLQT1 protein. Conclusions: We have identified LQTS-causing mutations of KVLQT1 in seven families. Five KVLQT1 mutations cause the truncation of KVLQT1 protein. These data further confirm that KVLQT1 mutations cause LQTS. The location and character of these mutations expand the types of mutation, confirm a mutational hot spot, and suggest that they act through a loss-of- function mechanism or a dominant-negative mechanism.",
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T1 - New mutations in the KVLQT1 potassium channel that cause long-QT syndrome

AU - Li, Hua

AU - Chen, Qiuyun

AU - Moss, Arthur J.

AU - Robinson, Jennifer

AU - Goytia, Veronica

AU - Perry, James C.

AU - Michael Vincent, G.

AU - Priori, Silvia G.

AU - Lehmann, Michael H.

AU - Denfield, Susan W.

AU - Duff, Desmond

AU - Kaine, Stephen

AU - Shimizu, Wataru

AU - Schwartz, Peter J.

AU - Wang, Qing

AU - Towbin, Jeffrey

PY - 1998/4/7

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N2 - Background: Long-QT syndrome (LQTS) is an inherited cardiac arrhythmia that causes sudden death in young, otherwise healthy people. Four genes for LQTS have been mapped to chromosome 11p15.5 (LQT1), 7q35-36 (LQ72), 3p21-24 (LQT3), and 4q25-27 (LQT4). Genes responsible for LQT1, LQT2, and LQT3 have been identified as cardiac potassium channel genes (KVLQT1, HERG) and the cardiac sodium channel gene (SCN5A). Methods and Results: After studying 115 families with LQTS, we used single-strand conformation polymorphism (SSCP) and DNA sequence analysis to identify mutations in the cardiac potassium channel gene, KVLQT1. Affected members of seven LQTS families were found to have new, previously unidentified mutations, including two identical missense mutations, four identical splicing mutations, and one 3-bp deletion. An identical splicing mutation was identified in affected members of four unrelated families (one Italian, one Irish, and two American), leading to an alternatively spliced form of KVLQT1. The 3-bp deletion arose de novo and occurs at an exon-intron boundary. This results in a single base deletion in the KVLQT1 cDNA sequence and alters splicing, leading to the truncation of KVLQT1 protein. Conclusions: We have identified LQTS-causing mutations of KVLQT1 in seven families. Five KVLQT1 mutations cause the truncation of KVLQT1 protein. These data further confirm that KVLQT1 mutations cause LQTS. The location and character of these mutations expand the types of mutation, confirm a mutational hot spot, and suggest that they act through a loss-of- function mechanism or a dominant-negative mechanism.

AB - Background: Long-QT syndrome (LQTS) is an inherited cardiac arrhythmia that causes sudden death in young, otherwise healthy people. Four genes for LQTS have been mapped to chromosome 11p15.5 (LQT1), 7q35-36 (LQ72), 3p21-24 (LQT3), and 4q25-27 (LQT4). Genes responsible for LQT1, LQT2, and LQT3 have been identified as cardiac potassium channel genes (KVLQT1, HERG) and the cardiac sodium channel gene (SCN5A). Methods and Results: After studying 115 families with LQTS, we used single-strand conformation polymorphism (SSCP) and DNA sequence analysis to identify mutations in the cardiac potassium channel gene, KVLQT1. Affected members of seven LQTS families were found to have new, previously unidentified mutations, including two identical missense mutations, four identical splicing mutations, and one 3-bp deletion. An identical splicing mutation was identified in affected members of four unrelated families (one Italian, one Irish, and two American), leading to an alternatively spliced form of KVLQT1. The 3-bp deletion arose de novo and occurs at an exon-intron boundary. This results in a single base deletion in the KVLQT1 cDNA sequence and alters splicing, leading to the truncation of KVLQT1 protein. Conclusions: We have identified LQTS-causing mutations of KVLQT1 in seven families. Five KVLQT1 mutations cause the truncation of KVLQT1 protein. These data further confirm that KVLQT1 mutations cause LQTS. The location and character of these mutations expand the types of mutation, confirm a mutational hot spot, and suggest that they act through a loss-of- function mechanism or a dominant-negative mechanism.

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