Kir 2.1 channelopathies: the Andersen–Tawil syndrome

  • Martin Tristani-Firouzi
  • Susan P. Etheridge
Invited Review


As a multisystem disorder, Andersen–Tawil syndrome (ATS) is rather unique in the family of channelopathies. The full spectrum of the disease is characterized by ventricular arrhythmias, dysmorphic features, and periodic paralysis. Most ATS patients have a mutation in the ion channel gene, KCNJ2, which encodes the inward rectifier K+ channel Kir2.1, a component of the inward rectifier I K1. I K1 provides repolarizing current during the most terminal phase of repolarization and is the primary conductance controlling the diastolic membrane potential. Thus, ATS is a disorder of cardiac repolarization. The chapter will discuss the most recent data concerning the genetic, cellular, and clinical data underlying this unique disorder.


Potassium channel KCNJ2 Inward rectifier Arrhythmia 


  1. 1.
    Ai T, Fujiwara Y, Tsuji K, Otani H, Nakano S, Kubo Y, Horie M (2002) Novel KCNJ2 mutation in familial periodic paralysis with ventricular dysrhythmia. Circulation 105:2592–2594CrossRefPubMedGoogle Scholar
  2. 2.
    Airey KJ, Etheridge SP, Tawil R, Tristani-Firouzi M (2009) Resuscitated sudden cardiac death in Andersen–Tawil syndrome. Heart Rhythm 6:1814–1817CrossRefPubMedGoogle Scholar
  3. 3.
    Andelfinger G, Tapper AR, Welch RC, Vanoye CG, George AL Jr, Benson DW (2002) KCNJ2 mutation results in Andersen syndrome with sex-specific cardiac and skeletal muscle phenotypes. Am J Hum Genet 71:663–668CrossRefPubMedGoogle Scholar
  4. 4.
    Andersen ED, Krasilnikoff PA, Overvad H (1971) Intermittent muscular weakness, extrasystoles, and multiple developmental anomalies. A new syndrome? Acta Paediatr Scand 60:559–564CrossRefPubMedGoogle Scholar
  5. 5.
    Bokenkamp R, Wilde AA, Schalij MJ, Blom NA (2007) Flecainide for recurrent malignant ventricular arrhythmias in two siblings with Andersen–Tawil syndrome. Heart Rhythm 4:508–511CrossRefPubMedGoogle Scholar
  6. 6.
    Chun TU, Epstein MR, Dick M 2nd, Andelfinger G, Ballester L, Vanoye CG, George AL Jr, Benson DW (2004) Polymorphic ventricular tachycardia and KCNJ2 mutations. Heart Rhythm 1:235–241CrossRefPubMedGoogle Scholar
  7. 7.
    Donaldson MR, Yoon G, Fu YH, Ptacek LJ (2004) Andersen–Tawil syndrome: a model of clinical variability, pleiotropy, and genetic heterogeneity. Ann Med 36(Suppl 1):92–97CrossRefPubMedGoogle Scholar
  8. 8.
    January CT, Riddle JM (1989) Early afterdepolarizations: mechanism of induction and block. A role for L-type Ca2+ current. Circ Res 64:977–990PubMedGoogle Scholar
  9. 9.
    Kannankeril PJ, Roden DM, Fish FA (2004) Suppression of bidirectional ventricular tachycardia and unmasking of prolonged QT interval with verapamil in Andersen's syndrome. J Cardiovasc Electrophysiol 15:119CrossRefPubMedGoogle Scholar
  10. 10.
    Klein R, Ganelin R, Marks JF, Usher P, Richards C (1963) J Periodic paralysis with cardiac arrhythmia. J Pediatr 62:371–385CrossRefPubMedGoogle Scholar
  11. 11.
    Kummer JL, Nair R, Krishnan SC (2006) Images in cardiovascular medicine. Bidirectional ventricular tachycardia caused by digitalis toxicity. Circulation 113:e156–e157CrossRefPubMedGoogle Scholar
  12. 12.
    Levi AJ, Dalton GR, Hancox JC, Mitcheson JS, Issberner J, Bates JA, Evans SJ, Howarth FC, Hobai IA, Jones JV (1997) Role of intracellular sodium overload in the genesis of cardiac arrhythmias. J Cardiovasc Electrophysiol 8:700–721CrossRefPubMedGoogle Scholar
  13. 13.
    Levitt LP, Rose LI, Dawson DM (1972) Hypokalemic periodic paralysis with arrhythmia. N Engl J Med 286:253–254PubMedCrossRefGoogle Scholar
  14. 14.
    Lisak RP, Lebeau J, Tucker SH, Rowland LP (1972) Hyperkalemic periodic paralysis and cardiac arrhythmia. Neurology 22:810–815PubMedGoogle Scholar
  15. 15.
    Lopes CM, Zhang H, Rohacs T, Jin T, Yang J, Logothetis DE (2002) Alterations in conserved Kir channel–PIP2 interactions underlie channelopathies. Neuron 34:933–944CrossRefPubMedGoogle Scholar
  16. 16.
    Miake J, Marban E, Nuss HB (2002) Biological pacemaker created by gene transfer. Nature 419:132–133CrossRefPubMedGoogle Scholar
  17. 17.
    Pellizzon OA, Kalaizich L, Ptacek LJ, Tristani-Firouzi M, Gonzalez MD (2008) Flecainide suppresses bidirectional ventricular tachycardia and reverses tachycardia-induced cardiomyopathy in Andersen–Tawil syndrome. J Cardiovasc Electrophysiol 19:95–97PubMedGoogle Scholar
  18. 18.
    Peters S, Schulze-Bahr E, Etheridge SP, Tristani-Firouzi M (2007) Sudden cardiac death in Andersen–Tawil syndrome. Europace 9:162–166CrossRefPubMedGoogle Scholar
  19. 19.
    Piccini J, Zaas A (2003) Cases from the Osler medical service at Johns Hopkins University. Digitalis toxicity with bidirectional ventricular tachycardia. Am J Med 115:70–71CrossRefPubMedGoogle Scholar
  20. 20.
    Plaster NM, Tawil R, Tristani-Firouzi M, Canun S, Bendahhou S, Tsunoda A, Donaldson MR, Iannaccone ST, Brunt E, Barohn R, Clark J, Deymeer F, George AL Jr, Fish FA, Hahn A, Nitu A, Ozdemir C, Serdaroglu P, Subramony SH, Wolfe G, Fu YH, Ptacek LJ (2001) Mutations in Kir2.1 cause the developmental and episodic electrical phenotypes of Andersen's syndrome. Cell 105:511–519CrossRefPubMedGoogle Scholar
  21. 21.
    Priori SG, Napolitano C, Tiso N, Memmi M, Vignati G, Bloise R, Sorrentino V, Danieli GA (2001) Mutations in the cardiac ryanodine receptor gene (hRyR2) underlie catecholaminergic polymorphic ventricular tachycardia. Circulation 103:196–200PubMedGoogle Scholar
  22. 22.
    Rowland LP, Lisak RP, Levitt LP, Dawson DM (1972) Periodic paralysis: K levels during arrhythmia. N Engl J Med 287:50PubMedGoogle Scholar
  23. 23.
    Sanchez-Chapula JA, Salinas-Stefanon E, Torres-Jacome J, Benavides-Haro DE, Navarro-Polanco RA (2001) Blockade of currents by the antimalarial drug chloroquine in feline ventricular myocytes. J Pharmacol Exp Ther 297:437–445PubMedGoogle Scholar
  24. 24.
    Schoonderwoerd BA, Wiesfeld AC, Wilde AA, van den Heuvel F, Van Tintelen JP, van den Berg MP, Van Veldhuisen DJ, Van Gelder IC (2006) A family with Andersen–Tawil syndrome and dilated cardiomyopathy. Heart Rhythm 3:1346–1350CrossRefPubMedGoogle Scholar
  25. 25.
    Seemann G, Sachse FB, Weiss DL, Ptacek LJ, Tristani-Firouzi M (2007) Modeling of I K1 mutations in human left ventricular myocytes and tissue. Am J Physiol Heart Circ Physiol 292:H549–H559CrossRefPubMedGoogle Scholar
  26. 26.
    Silva J, Rudy Y (2003) Mechanism of pacemaking in I K1-downregulated myocytes. Circ Res 92:261–263CrossRefPubMedGoogle Scholar
  27. 27.
    Tristani-Firouzi M (2004) Polymorphic ventricular tachycardia associated with mutations in KCNJ2. Heart Rhythm 1:242–243CrossRefPubMedGoogle Scholar
  28. 28.
    Tristani-Firouzi M, Jensen JL, Donaldson MR, Sansone V, Meola G, Hahn A, Bendahhou S, Kwiecinski H, Fidzianska A, Plaster N, Fu YH, Ptacek LJ, Tawil R (2002) Functional and clinical characterization of KCNJ2 mutations associated with LQT7 (Andersen syndrome). J Clin Invest 110:381–388PubMedGoogle Scholar
  29. 29.
    Tsuboi M, Antzelevitch C (2006) Cellular basis for electrocardiographic and arrhythmic manifestations of Andersen–Tawil syndrome (LQT7). Heart Rhythm 3:328–335CrossRefPubMedGoogle Scholar
  30. 30.
    Wang Z, Yue L, White M, Pelletier G, Nattel S (1998) Differential distribution of inward rectifier potassium channel transcripts in human atrium versus ventricle. Circulation 98:2422–2428PubMedGoogle Scholar
  31. 31.
    Weingart R, Kass RS, Tsien RW (1978) Is digitalis inotropy associated with enhanced slow inward calcium current? Nature 273:389–392CrossRefPubMedGoogle Scholar
  32. 32.
    Yoon G, Oberoi S, Tristani-Firouzi M, Etheridge SP, Quitania L, Kramer JH, Miller BL, Fu YH, Ptacek LJ (2006) Andersen–Tawil syndrome: prospective cohort analysis and expansion of the phenotype. Am J Med Genet 140:312–321CrossRefPubMedGoogle Scholar
  33. 33.
    Zhang L, Benson DW, Tristani-Firouzi M, Ptacek LJ, Tawil R, Schwartz PJ, George AL, Horie M, Andelfinger G, Snow GL, Fu YH, Ackerman MJ, Vincent GM (2005) Electrocardiographic features in Andersen–Tawil syndrome patients with KCNJ2 mutations: characteristic T–U-wave patterns predict the KCNJ2 genotype. Circulation 111:2720–2726CrossRefPubMedGoogle Scholar
  34. 34.
    Zobel C, Cho HC, Nguyen TT, Pekhletski R, Diaz RJ, Wilson GJ, Backx PH (2003) Molecular dissection of the inward rectifier potassium current (I K1) in rabbit cardiomyocytes: evidence for heteromeric co-assembly of Kir2.1 and Kir2.2. J Physiol 550:365–372CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  1. 1.Division of Pediatric CardiologyUniversity of Utah School of MedicineSalt Lake CityUSA

Personalised recommendations