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Functional and clinical characterization of a mutation in KCNJ2 associated with Andersen-Tawil syndrome
  1. C-W Lu1,
  2. J-H Lin2,
  3. Y S Rajawat3,
  4. H Jerng4,
  5. T G Rami3,
  6. X Sanchez5,
  7. G DeFreitas6,
  8. B Carabello6,
  9. F DeMayo7,
  10. D L Kearney8,
  11. G Miller9,
  12. H Li5,
  13. P J Pfaffinger4,
  14. N E Bowles5,
  15. D S Khoury2,3,
  16. J A Towbin2,5,10
  1. 1Department of Pediatrics, Shin Kong Wu Ho-Su Memorial Hospital, Taipei, Taiwan
  2. 2Cardiovascular Sciences Program, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
  3. 3Center for Experimental Cardiac Electrophysiology, Department of Medicine (Section of Cardiology), Baylor College of Medicine, Houston, TX, USA
  4. 4Neuroscience, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
  5. 5Department of Pediatrics (Section of Cardiology), Baylor College of Medicine, Houston, TX, USA
  6. 6General Medicine, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
  7. 7Department of Cell Biology, Baylor College of Medicine, Houston, TX, USA
  8. 8Department of Pathology, Baylor College of Medicine, Houston, TX, USA
  9. 9Department of Pediatrics, Section of Neurology, Yale University School of Medicine, New Haven, CT, USA
  10. 10Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
  1. Correspondence to:
 Dr J A Towbin
 Department of Pediatrics (Cardiology), Baylor College of Medicine, 6621 Fannin Street, FC.430.09, Houston, TX 77030, USA; jtowbin{at}bcm.tmc.edu

Abstract

Background: Andersen-Tawil syndrome (ATS) is a rare inherited disorder, characterised by periodic paralysis, cardiac dysarrhythmias, and dysmorphic features, and is caused by mutations in the gene KCNJ2, which encodes the inward rectifier potassium channel, Kir2.1. This study sought to analyse KCNJ2 in patients with familial ATS and to determine the functional characteristics of the mutated gene.

Methods and results: We screened a family with inherited ATS for the mutation in KCNJ2, using direct DNA sequencing. A missense mutation (T75R) of Kir2.1, located in the highly conserved cytoplasmic N-terminal domain, was identified in three affected members of this family. Using the Xenopus oocyte expression system and whole cell voltage clamp analyses, we found that the T75R mutant was non-functional and possessed a strong dominant negative effect when co-expressed with the same amount of wild type Kir2.1. Transgenic (Tg) mice expressing the mutated form of Kir2.1 in the heart had prolonged QTc intervals compared with mice expressing the wild type protein. Ventricular tachyarrhythmias were observed in 5 of 14 T75R-Tg mice compared with 1 of 7 Wt-Tg and none of 6 non-transgenic littermates. In three of five T75R-Tg mice with ventricular tachycardia, their ECG disclosed bidirectional tachycardia as in our proband.

Conclusions: The in vitro studies revealed that the T75R mutant of Kir2.1 had a strong dominant negative effect in the Xenopus oocyte expression system. It still preserved the ability to co-assemble and traffic to the cell membrane in mammalian cells. For in vivo studies, the T75R-Tg mice had bidirectional ventricular tachycardia after induction and longer QT intervals.

  • ATS, Andersen-Tawil syndrome
  • IK1, inward rectifier current
  • PIP2, phosphatidylinositol 4,5-bisphosphate
  • PVC, premature ventricular contraction
  • QTc, corrected QT interval
  • RBBB, right bundle branch block
  • Tg, transgenic
  • VT, ventricular tachycardia
  • WT, wild type
  • arrhythmia
  • genetics
  • ion channels

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Footnotes

  • Published Online First 29 March 2006

  • The first two authors contributed equally contributed equally to this work.

  • Competing interests: there are no competing interests.

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