Screening for mutations and polymorphisms in the genes KCNH2 and KCNE2 encoding the cardiac HERG/MiRP1 ion channel: implications for acquired and congenital long Q-T syndrome.

BACKGROUND The voltage-gated, rapid-delayed rectifier current (I(Kr)) is important for repolarization of the heart, and mutations in the genes coding for the K+-ion channel conducting this current, i.e., KCNH2 for the alpha-subunit HERG and KCNE2 for the beta-subunit MiRP1, cause acquired and congenital long Q-T syndrome (LQTS) and other cardiac arrhythmias. METHODS We developed a robust single-strand conformation polymorphism-heteroduplex screening analysis, with identical thermocycling conditions for all PCR reactions, covering all of the coding exons in KCNH2 and KCNE2. The method was used to screen 40 unrelated LQTS patients. RESULTS Eleven mutations, of which six were novel, were found in KCNH2. Interestingly, six mutations were found in the region of the gene coding for the Per-Arnt-Sim (PAS) and PAS-S1 regions of the HERG protein, stressing the need to examine the entire gene when screening for mutations. No mutations were found in KCNE2, suggesting that direct involvement of MiRP1 in LQTS is rare. Furthermore, four novel single-nucleotide polymorphisms (SNPs) and one amino acid polymorphism (R1047L) were identified in KCNH2, and one novel SNP and one previously known amino acid polymorphism (T8A) were found in KCNE2. CONCLUSIONS The potential role of rare polymorphisms in the HERG/MiRP1 K+-channel should be clarified with respect to drug interactions and susceptibility to arrhythmia and sudden death.

[1]  S. Priori,et al.  A molecular link between the sudden infant death syndrome and the long-QT syndrome. , 2000, The New England journal of medicine.

[2]  Jørgen K. Kanters,et al.  Long QT syndrome with a high mortality rate caused by a novel G572R missense mutation in KCNH2 , 2000, Clinical genetics.

[3]  S. Viskin.  Long QT syndromes and torsade de pointes , 1999, The Lancet.

[4]  D. Roden,et al.  A plethora of mechanisms in the HERG-related long QT syndrome. Genetics meets electrophysiology. , 1999, Cardiovascular research.

[5]  M. Sanguinetti,et al.  Biophysical Properties and Molecular Basis of Cardiac Rapid and Slow Delayed Rectifier Potassium Channels , 1999, Cellular Physiology and Biochemistry.

[6]  Michael Christiansen,et al.  Recessive Romano-Ward syndrome associated with compound heterozygosity for two mutations in the KVLQT1 gene , 1999, European Journal of Human Genetics.

[7]  G. Marone,et al.  Cardiac ion channels and antihistamines: possible mechanisms of cardiotoxicity , 1999, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[8]  H. Knoblauch,et al.  QT interval is linked to 2 long-QT syndrome loci in normal subjects. , 1999, Circulation.

[9]  M. Keating,et al.  MiRP1 Forms IKr Potassium Channels with HERG and Is Associated with Cardiac Arrhythmia , 1999, Cell.

[10]  M. Sanguinetti,et al.  Long QT Syndrome-associated Mutations in the Per-Arnt-Sim (PAS) Domain of HERG Potassium Channels Accelerate Channel Deactivation* , 1999, The Journal of Biological Chemistry.

[11]  M. Sanguinetti.  Dysfunction of Delayed Rectifier Potassium Channels in an Inherited Cardiac Arrhythmia , 1999, Annals of the New York Academy of Sciences.

[12]  P. Coumel,et al.  C-terminal HERG mutations: the role of hypokalemia and a KCNQ1-associated mutation in cardiac event occurrence. , 1999, Circulation.

[13]  W. Kübler,et al.  Inhibitory effects of the class III antiarrhythmic drug amiodarone on cloned HERG potassium channels , 1999, Naunyn-Schmiedeberg's Archives of Pharmacology.

[14]  S. Priori,et al.  Low penetrance in the long-QT syndrome: clinical impact. , 1999, Circulation.

[15]  K. Hayashi,et al.  Recent enhancements in SSCP. , 1999, Genetic analysis : biomolecular engineering.

[16]  J. Vuust,et al.  High‐throughput single‐strand conformation polymorphism analysis by automated capillary electrophoresis: Robust multiplex analysis and pattern‐based identification of allelic variants , 1999, Human mutation.

[17]  A. Busch,et al.  The IKs channel: coassembly of IsK (minK) and KvLQT1 proteins. , 1999, Reviews of physiology, biochemistry and pharmacology.

[18]  E. Rosenthal,et al.  Prolongation of the QT interval and the sudden infant death syndrome. , 1998, The New England journal of medicine.

[19]  Yusuke Nakamura,et al.  Genomic organization and mutational analysis of KVLQT1, a gene responsible for familial long QT syndrome , 1998, Human Genetics.

[20]  D. Rampe,et al.  The antipsychotic agent sertindole is a high affinity antagonist of the human cardiac potassium channel HERG. , 1998, The Journal of pharmacology and experimental therapeutics.

[21]  A. Brown,et al.  Blockade of HERG and Kv1.5 by ketoconazole. , 1998, The Journal of pharmacology and experimental therapeutics.

[22]  M. Keating,et al.  Genomic structure of three long QT syndrome genes: KVLQT1, HERG, and KCNE1. , 1998, Genomics.

[23]  P. Schwartz,et al.  Prolongation of the QT interval and the sudden infant death syndrome. , 1998, The New England journal of medicine.

[24]  M J Ackerman,et al.  The long QT syndrome: ion channel diseases of the heart. , 1998, Mayo Clinic proceedings.

[25]  G. Ginsburg,et al.  Multiple different missense mutations in the pore region of HERG in patients with long QT syndrome , 1998, Human Genetics.

[26]  M. Furutani,et al.  Novel missense mutation (G601S) of HERG in a Japanese long QT syndrome family , 1998, Human mutation.

[27]  Yusuke Nakamura,et al.  Genomic organization and mutational analysis of HERG, a gene responsible for familial long QT syndrome , 1998, Human Genetics.

[28]  P. Coumel,et al.  KVLQT1 C-terminal missense mutation causes a forme fruste long-QT syndrome. , 1997, Circulation.

[29]  M. Sanguinetti,et al.  Mutations in the hminK gene cause long QT syndrome and suppress lKs function , 1997, Nature Genetics.

[30]  R. Axton,et al.  Combined SSCP/heteroduplex analysis in the screening for PAX6 mutations. , 1997, Molecular and cellular probes.

[31]  Y. Yazaki,et al.  Four novel KVLQT1 and four novel HERG mutations in familial long-QT syndrome. , 1997, Circulation.

[32]  B Attali,et al.  The inhibitory effect of the antipsychotic drug haloperidol on HERG potassium channels expressed in Xenopus oocytes , 1997, British journal of pharmacology.

[33]  G. Landes,et al.  Positional cloning of a novel potassium channel gene: KVLQT1 mutations cause cardiac arrhythmias , 1996, Nature Genetics.

[34]  S. Priori,et al.  Long QT syndrome patients with mutations of the SCN5A and HERG genes have differential responses to Na+ channel blockade and to increases in heart rate. Implications for gene-specific therapy. , 1995, Circulation.

[35]  M. Sanguinetti,et al.  A mechanistic link between an inherited and an acquird cardiac arrthytmia: HERG encodes the IKr potassium channel , 1995, Cell.

[36]  E. Green,et al.  A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome , 1995, Cell.