KCNJ2 mutations in arrhythmia patients referred for LQT testing: A mutation T305A with novel effect on rectification properties

Lee L. Eckhardt, Amanda L. Farley, Esther Rodriguez, Karen Ruwaldt, Daniel Hammill, David J. Tester, Michael J. Ackerman, Jonathan C. Makielski

Research output: Contribution to journalArticlepeer-review

32 Scopus citations


Background: Loss-of-function mutations in the KCNJ2 cause ∼50% of Andersen-Tawil Syndrome (ATS) characterized by a classic triad of periodic paralysis, ventricular arrhythmia, and dysmorphic features. Do KCNJ2 mutations occur in patients lacking this triad and lacking a family history of ATS? Objectives: The purpose of this study was to identify and characterize mutations in the KCNJ2-encoded inward rectifier potassium channel Kir2.1 from patients referred for genetic arrhythmia testing. Methods: Mutational analysis of KCNJ2 was performed for 541 unrelated patients. The mutations were made in wild type (WT) and expressed in COS-1 cells and voltage clamped for ion currents. Results: Three novel missense mutations (R67Q, R85W, and T305A) and one known mutation (T75M) were identified in 4/249 (1.6%) patients genotype-negative for other known arrhythmia genes with overall incidence 4/541 (0.74%). They had prominent U-waves, marked ventricular ectopy, and polymorphic ventricular tachycardia but no facial/skeletal abnormalities. Periodic paralysis was present in only one case. Outward current was decreased to less than 5% of WT for all mutants expressed alone. Co-expression with WT (simulating heterozygosity) caused a marked dominant negative effect for T75M and R82W, no dominant negative effect for R67Q, and a novel selective enhancement of inward rectification for T305A. Conclusions: KCNJ2 loss of function mutations were found in ∼1% of patients referred for genetic arrhythmia testing that lacked criteria for ATS. Characterization of three new mutations identified a novel dominant negative effect selectively reducing outward current for T305A. These results extend the range of clinical phenotype and molecular phenotype associated with KCNJ2 mutations.

Original languageEnglish (US)
Pages (from-to)323-329
Number of pages7
JournalHeart rhythm
Issue number3
StatePublished - Mar 2007


  • Gene expression
  • Gene testing, Inward rectification, KIR2.1
  • Ion channels
  • K-channel
  • Long QT syndrome
  • Ventricular Arrhythmia

ASJC Scopus subject areas

  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)


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