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Isolation and Kv Channel Recordings in Murine Atrial and Ventricular Cardiomyocytes
11:33

Isolation and Kv Channel Recordings in Murine Atrial and Ventricular Cardiomyocytes

Published on: March 12, 2013

A common polymorphism associated with antibiotic-induced cardiac arrhythmia

F Sesti1, G W Abbott, J Wei

  • 1Departments of Pediatrics and Cellular and Molecular Physiology, Boyer Center for Molecular Medicine, Yale University School of Medicine, New Haven, CT 06536, USA.

Proceedings of the National Academy of Sciences of the United States of America
|September 14, 2000
PubMed

Insights

Genetic variants in KCNE2, encoding MinK-related peptide 1 (MiRP1), contribute to drug-induced long QT syndrome (LQTS). Common variations can increase risk for life-threatening drug reactions, even if clinically silent initially.

Area of Science:

  • Cardiovascular Genetics
  • Pharmacogenomics
  • Ion Channel Physiology

Background:

  • Drug-induced long QT syndrome (LQTS) is a significant cause of sudden cardiac death with complex origins.
  • KCNE2 gene encodes the MinK-related peptide 1 (MiRP1) subunit of the cardiac potassium channel I(Kr), implicated in inherited LQTS.

Purpose of the Study:

  • To investigate the role of KCNE2 variants in patients diagnosed with drug-induced LQTS.
  • To determine the functional consequences of identified KCNE2 mutations and single-nucleotide polymorphisms (SNPs) on cardiac potassium channel function and drug response.

Main Methods:

  • Genetic analysis of the KCNE2 gene in 98 patients with drug-induced LQTS.
  • Functional characterization of mutant and SNP-carrying channels using electrophysiology to assess potassium flux and drug sensitivity.
  • Comparison of wild-type and variant channel behavior in response to therapeutic drug levels.

Main Results:

  • Three patients with sporadic mutations in KCNE2 were identified.
  • One patient with sulfamethoxazole-associated LQTS carried a common KCNE2 SNP (rs number not provided).
  • Mutant channels exhibited reduced baseline potassium current, while SNP-carrying channels were inhibited by sulfamethoxazole at therapeutic concentrations, unlike wild-type channels.

Conclusions:

  • Allelic variants of MiRP1 (encoded by KCNE2) are a significant contributing factor to drug-induced LQTS through diverse mechanisms.
  • Common KCNE2 sequence variations can predispose individuals to life-threatening drug reactions, remaining asymptomatic prior to drug exposure.

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