(Circulation. 1999;100:1264-1267.)
© 1999 American Heart Association, Inc.
Brief Rapid Communication |
Homozygous Premature Truncation of the HERG Protein
The Human HERG Knockout
From the Departments of Pediatric Cardiology, University Hospital and Wilhelmina Children's Hospital (T.H., N.S.), Utrecht; the Departments of Clinical Genetics (M.A., K.v.d.L., M.M.), Cardiovascular Pathology (A.v.d.W.), and Clinical and Experimental Cardiology (A.W.), Academic Medical Center, Amsterdam; and the Departments of Medical Genetics (P.v.T.) and Cardiology (A.W.), University Medical Centre Utrecht, Utrecht; and The Interuniversity Cardiology Institute, The Netherlands.
Correspondence to Dr Wilde, Department of Clinical and Experimental Cardiology, AMC Amsterdam, PO BOX 22700, 1100 DE Amsterdam, the Netherlands. E-mail a.a.wilde{at}AMC.UVA.NL
Background—In long-QT syndrome (LQTS), heterozygosity for a mutation in 1 of the K+ channel genes leads to prolongation of the cardiac action potential, because the aberrant protein exhibits "loss of function." HERG, which is involved in LQT2, is the gene encoding the rapid component of the delayed rectifier, IKr.
Methods and Results—In a consanguineous family, a stillbirth was followed by the premature birth of a child in distress due to ventricular arrhythmia in the presence of QT prolongation. LQTS was diagnosed, ß-blocker therapy was begun, and a pacemaker was implanted. She developed well and remained symptom-free for 1.5 years. In the index patient, we identified a duplication of bp 558 to 600 in exon 4 of HERG on both alleles. This will result in a frameshift and a premature stop codon before the S1 domain of the HERG protein. Because it is present on both alleles, no functional IKr is anticipated. The same mutation was found heterozygously in both parents and homozygously in the stillborn brother.
Conclusions—It is concluded that absence of IKr gives rise to a severe cardiac phenotype, with no indication of malfunction of any other organ.
Key Words: genetics • torsade de pointes • arrhythmia
This article has been cited by other articles:
 |
|
 |
|
  W. T. Clusin Mechanisms of calcium transient and action potential alternans in cardiac cells and tissues Am J Physiol Heart Circ Physiol, January 1, 2008; 294(1): H1 - H10. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Medeiros-Domingo, T. Kaku, D. J. Tester, P. Iturralde-Torres, A. Itty, B. Ye, C. Valdivia, K. Ueda, S. Canizales-Quinteros, M. T. Tusie-Luna, et al. SCN4B-Encoded Sodium Channel 4 Subunit in Congenital Long-QT Syndrome Circulation, July 10, 2007; 116(2): 134 - 142. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Arnaout, T. Ferrer, J. Huisken, K. Spitzer, D. Y. R. Stainier, M. Tristani-Firouzi, and N. C. Chi Zebrafish model for human long QT syndrome PNAS, July 3, 2007; 104(27): 11316 - 11321. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. J. Heradien, A. Goosen, L. Crotti, G. Durrheim, V. Corfield, P. A. Brink, and P. J. Schwartz Does Pregnancy Increase Cardiac Risk for LQT1 Patients With the KCNQ1-A341V Mutation? J. Am. Coll. Cardiol., October 3, 2006; 48(7): 1410 - 1415. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Kaab and E. Schulze-Bahr Susceptibility genes and modifiers for cardiac arrhythmias Cardiovasc Res, August 15, 2005; 67(3): 397 - 413. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
D. J. Milan and C. A. MacRae Animal models for arrhythmias Cardiovasc Res, August 15, 2005; 67(3): 426 - 437. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 Recurrent syncope Postgrad. Med. J., March 1, 2005; 81(953): 202 - 202. [Full Text] [PDF]
|
|
|
|
 |
|
 A. D.J. Ten Harkel, M. Witsenburg, P. L. de Jong, L. Jordaens, M. Wijman, and A. A.M. Wilde Efficacy of an implantable cardioverter-defibrillator in a neonate with LQT3 associated arrhythmias Europace, January 1, 2005; 7(1): 77 - 84. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
W. P. McNair, L. Ku, M. R.G. Taylor, P. R. Fain, D. Dao, E. Wolfel, L. Mestroni, and the Familial Cardiomyopathy Registry Research Grou SCN5A Mutation Associated With Dilated Cardiomyopathy, Conduction Disorder, and Arrhythmia Circulation, October 12, 2004; 110(15): 2163 - 2167. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
P. J. Schwartz Stillbirths, Sudden Infant Deaths, and Long-QT Syndrome: Puzzle or Mosaic, the Pieces of the Jigsaw Are Being Fitted Together Circulation, June 22, 2004; 109(24): 2930 - 2932. [Full Text] [PDF]
|
|
|
|
|
|
S. S. Chugh, O. Senashova, A. Watts, P. T. Tran, Z. Zhou, Q. Gong, J. L. Titus, and S. J. Hayflick Postmortem molecular screening in unexplained sudden death J. Am. Coll. Cardiol., May 5, 2004; 43(9): 1625 - 1629. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
J.-M. Lupoglazoff, I. Denjoy, E. Villain, V. Fressart, F. Simon, A. Bozio, M. Berthet, N. Benammar, B. Hainque, and P. Guicheney Long QT syndrome in neonates: Conduction disorders associated with HERG mutations and sinus bradycardia with KCNQ1 mutations J. Am. Coll. Cardiol., March 3, 2004; 43(5): 826 - 830. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. P. Lees-Miller, J. Guo, J. R. Somers, D. E. Roach, R. S. Sheldon, D. E. Rancourt, and H. J. Duff Selective Knockout of Mouse ERG1 B Potassium Channel Eliminates IKr in Adult Ventricular Myocytes and Elicits Episodes of Abrupt Sinus Bradycardia Mol. Cell. Biol., March 15, 2003; 23(6): 1856 - 1862. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 C. R. Bezzina, M. B. Rook, W.A. Groenewegen, L. J. Herfst, A. C. van der Wal, J. Lam, H. J. Jongsma, A. A.M. Wilde, and M. M.A.M. Mannens Compound Heterozygosity for Mutations (W156X and R225W) in SCN5A Associated With Severe Cardiac Conduction Disturbances and Degenerative Changes in the Conduction System Circ. Res., February 7, 2003; 92(2): 159 - 168. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. R Bezzina and H. L Tan Pharmacological rescue of mutant ion channels Cardiovasc Res, August 1, 2002; 55(2): 229 - 232. [Full Text] [PDF]
|
|
|
|
|
|
J.M. Lupoglazoff, T. Cheav, G. Baroudi, M. Berthet, I. Denjoy, B. Cauchemez, F. Extramiana, M. Chahine, and P. Guicheney Homozygous SCN5A Mutation in Long-QT Syndrome With Functional Two-to-One Atrioventricular Block Circ. Res., July 20, 2001; 89 (2): e16 - e21. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. E. Clancy and Y. Rudy Cellular consequences of HERG mutations in the long QT syndrome: precursors to sudden cardiac death Cardiovasc Res, May 1, 2001; 50(2): 301 - 313. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Thomas, G. Wendt-Nordahl, K. Röckl, E. Ficker, A. M. Brown, and J. Kiehn High-Affinity Blockade of Human Ether-A-Go-Go-Related Gene Human Cardiac Potassium Channels by the Novel Antiarrhythmic Drug BRL-32872 J. Pharmacol. Exp. Ther., April 12, 2001; 297(2): 753 - 761. [Abstract] [Full Text]
|
|
|
|
|
|
B. London, A. A.M. Wilde, M. M.A.M. Mannens, M. Alders, K. van der Lip, T. M. Hoorntje, N. Sreeram, P. van Tintelen, and A. van der Wal A Knockout May Not Always Be a Knockout Response Circulation, October 31, 2000; 102 (18): e122 - e122. [Full Text] [PDF]
|
|
|
|
|
|
I. Splawski, J. Shen, K. W. Timothy, M. H. Lehmann, S. Priori, J. L. Robinson, A. J. Moss, P. J. Schwartz, J. A. Towbin, G. M. Vincent, et al. Spectrum of Mutations in Long-QT Syndrome Genes : KVLQT1, HERG, SCN5A, KCNE1, and KCNE2 Circulation, September 5, 2000; 102(10): 1178 - 1185. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C.-E. Chiang and D. M. Roden The long QT syndromes: genetic basis and clinical implications J. Am. Coll. Cardiol., July 1, 2000; 36(1): 1 - 12. [Abstract] [Full Text] [PDF]
|
|