Characterization of a KCNQ1/KVLQT1 polymorphism in Asian families with LQT2

Implications for genetic testing

Dipika Sharma, Kathryn A. Glatter, V. Timofeyev, Dipika Tuteja, Zhao Zhang, Jennifer Rodriguez, David J. Tester, Reginald Low, Melvin M. Scheinman, Michael John Ackerman, Nipavan Chiamvimonvat

Research output: Contribution to journalArticle

30 Citations (Scopus)

Abstract

Congenital long QT syndrome (LQTS) is a genetic disease that predisposes affected individuals to arrhythmias, syncope, and sudden death. Mutations in several ion channel genes have been discovered in different families with LQTS: KCNQ1 (KVLQT1, LQT1), KCNH2 (HERG, LQT2), SCN5A (LQT3), KCNE1 (minK, LQT5), and KCNE2 (MiRP1, LQT6). Previously, the P448R-KVLQT1 missense mutation has been reported as an LQT1-causing mutation. In this report, we demonstrate the presence of the P448R polymorphism in two, unrelated Chinese LQTS families. Although absent from 500 reference alleles derived from 150 white and 100 African-American subjects, P448R was present in 14% of healthy Chinese volunteers. Given the inconsistencies between the genotype (LQT1) and clinical phenotype (LQT2) in our two LQTS families, together with the finding that the P448R appears to be a common, ethnic-specific polymorphism, mutational analysis was extended to the other LQTS-causing genes resulting in the identification of distinct HERG missense mutations in each of these two families. Heterologous expression of P448R-KVLQT1 yielded normal, wild-type (WT) currents. In contrast, the two unique HERG mutations resulted in dominant-negative suppression of the WT HERG channel. Our study has profound implications for those engaged in genetic research. Importantly, one child of the original proband was initially diagnosed with LQT1 based upon the presence of P448R-KVLQT1 and was treated with beta-blockers. However, he did not possess the subsequently determined LQT2-causing mutation. On the other hand, his untreated P448R-negative brother harbored the true, disease-causing HERG mutation. These findings underscore the importance of distinguishing channel polymorphisms from mutations pathogenic for LQTS and emphasize the importance of using appropriate ethnically matched controls in the genotypic analysis of LQTS.

Original languageEnglish (US)
Pages (from-to)79-89
Number of pages11
JournalJournal of Molecular and Cellular Cardiology
Volume37
Issue number1
DOIs
StatePublished - Jul 2004

Fingerprint

Long QT Syndrome
Genetic Testing
Mutation
Missense Mutation
Mink
Genetic Research
Inborn Genetic Diseases
Syncope
Sudden Death
Ion Channels
African Americans
Genes
Cardiac Arrhythmias
Siblings
Healthy Volunteers
Alleles
Genotype
Phenotype

Keywords

  • Genetic disease
  • HERG mutation
  • LQTS

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

Cite this

Characterization of a KCNQ1/KVLQT1 polymorphism in Asian families with LQT2 : Implications for genetic testing. / Sharma, Dipika; Glatter, Kathryn A.; Timofeyev, V.; Tuteja, Dipika; Zhang, Zhao; Rodriguez, Jennifer; Tester, David J.; Low, Reginald; Scheinman, Melvin M.; Ackerman, Michael John; Chiamvimonvat, Nipavan.

In: Journal of Molecular and Cellular Cardiology, Vol. 37, No. 1, 07.2004, p. 79-89.

Research output: Contribution to journalArticle

Sharma, D, Glatter, KA, Timofeyev, V, Tuteja, D, Zhang, Z, Rodriguez, J, Tester, DJ, Low, R, Scheinman, MM, Ackerman, MJ & Chiamvimonvat, N 2004, 'Characterization of a KCNQ1/KVLQT1 polymorphism in Asian families with LQT2: Implications for genetic testing', Journal of Molecular and Cellular Cardiology, vol. 37, no. 1, pp. 79-89. https://doi.org/10.1016/j.yjmcc.2004.03.015
Sharma, Dipika ; Glatter, Kathryn A. ; Timofeyev, V. ; Tuteja, Dipika ; Zhang, Zhao ; Rodriguez, Jennifer ; Tester, David J. ; Low, Reginald ; Scheinman, Melvin M. ; Ackerman, Michael John ; Chiamvimonvat, Nipavan. / Characterization of a KCNQ1/KVLQT1 polymorphism in Asian families with LQT2 : Implications for genetic testing. In: Journal of Molecular and Cellular Cardiology. 2004 ; Vol. 37, No. 1. pp. 79-89.
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