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Gene Review

KCNH2  -  potassium channel, voltage gated eag...

Homo sapiens

Synonyms: ERG, ERG-1, ERG1, Eag homolog, Eag-related protein 1, ...
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Disease relevance of KCNH2

  • OBJECTIVES: The purpose of this research was to determine whether an intronic variant (T1945+6C) in KCNH2 is a disease-causing mutation, and if expanded phenotyping criteria produce improved identification of long QT syndrome (LQTS) patients [1].
  • Role of a KCNH2 polymorphism (R1047 L) in dofetilide-induced Torsades de Pointes [2].
  • Short QT syndrome and atrial fibrillation caused by mutation in KCNH2 [3].
  • CONCLUSIONS: We demonstrate a novel genetic and biophysical mechanism responsible for sudden death in infants, children, and young adults caused by mutations in KCNH2 [4].
  • The occurrence of sudden cardiac death in the first 12 months of life in 2 patients suggests the possibility of a link between KCNH2 gain of function mutations and sudden infant death syndrome [4].
  • Advances in understanding the structural basis of hERG gating, its traffic to the cell surface, and the molecular architecture involved in drug-block of hERG, are providing the foundation for rational treatment and prevention of hERG associated long QT syndrome [5].

Psychiatry related information on KCNH2


High impact information on KCNH2

  • MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia [8].
  • Unlike channels formed only with HERG, mixed complexes resemble native cardiac IKr channels in their gating, unitary conductance, regulation by potassium, and distinctive biphasic inhibition by the class III antiarrhythmic E-4031 [8].
  • METHODS: We determined the genotypes of 541 of 1378 members of 38 families enrolled in the International Long-QT Syndrome Registry: 112 had mutations at the LQT1 locus, 72 had mutations at the LQT2 locus, and 62 had mutations at the LQT3 locus [9].
  • The HERG voltage-dependent K+ channel plays a role in cardiac electrical excitability, and when defective, it underlies one form of the long QT syndrome [10].
  • Crystal structure and functional analysis of the HERG potassium channel N terminus: a eukaryotic PAS domain [10].

Chemical compound and disease context of KCNH2


Biological context of KCNH2

  • Downregulation of the HERG (KCNH2) K(+) channel by ceramide: evidence for ubiquitin-mediated lysosomal degradation [16].
  • OBJECTIVE: To determine whether the amino acid 897 threonine (T) to lysine (K) polymorphism of the KCNH2 (HERG) potassium channel influences channel performance or patient phenotype [17].
  • 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 [18].
  • 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 [18].
  • No associations with KCNH2 genotype status were detected [19].

Anatomical context of KCNH2

  • We conclude that KCNH2 channels play a fundamental role in the control of motility patterns in human jejunum through their ability to modulate the electrical behavior of smooth muscle cells [20].
  • In vitro expression of the codon Y667X variant in Xenopus oocyte suggests that the autosomal dominant variant does not function in a dominant/negative manner and cannot co-assemble to form a channel, resulting in a reduction of the KCNH2 current, and an extension of the QT interval [21].
  • Species diversity and peptide toxins blocking selectivity of ether-a-go-go-related gene subfamily K+ channels in the central nervous system [22].
  • The accelerated inactivation time course of HERG/MiRP1(V65M) channels may decrease I(Kr) current density of myocardial cells, thereby impairing the ability of myocytes to repolarize in response to sudden membrane depolarizations such as extrasystoles [23].
  • Furthermore, HERG could not induce currents in COS-1 cells co-expressed with the D77N mutant and HERG (the human form of ERG) [24].

Associations of KCNH2 with chemical compounds

  • Low concentrations of the KCNH2 blockers E-4031 (10(-8) M) and MK-499 (3 x 10(-8) M) increased phasic contractile amplitude and the number of spikes per slow wave [20].
  • The syndrome was associated with a novel KCNH2 missense mutation, G572R, causing the substitution of a glycine residue at position 572, at the end of the S5 transmembrane segment of the HERG K(+)-channel, with an arginine residue [25].
  • Cyclic AMP regulates the HERG K(+) channel by dual pathways [26].
  • The mechanism of thyrotropin-releasing hormone (TRH)-induced ether-a-go-go-related gene (erg) K+ current modulation was investigated with the perforated-patch whole-cell technique in clonal somatomammotroph GH3/B6 cells [27].
  • All HERG channels had similar sensitivity to block by cisapride [28].

Physical interactions of KCNH2

  • The summation of cAMP-mediated effects is a net diminution of the effective current, but when HERG is complexed with with the K(+) channel accessory proteins MiRP1 or minK, the stimulatory effects of cAMP are favored [26].
  • Native GM130 and stably expressed HERG were co-immunoprecipitated from HEK-293 cells using GM130 antibodies [29].

Co-localisations of KCNH2

  • Expression studies in Chinese hamster ovary cells revealed that mutant and wild-type MiRP1 co-localized with HERG subunits and formed functional channels [23].
  • We show that FKBP38 immunoprecipitates and co-localizes with HERG in our cellular system [30].

Regulatory relationships of KCNH2

  • In the present retrospective study, we found that patients carrying mutations in the KCNQ1 gene responded better to beta-adrenergic blocking agents than those with KCNH2 mutations (12 of 13 vs 1 of 5; P = 0.0077, Fisher's exact test) [31].
  • Normal function of HERG K+ channels expressed in HEK293 cells requires basal protein kinase B activity [32].
  • When HERG was co-expressed with the accessory subunit KCNE2, an IC50 value of 52 microM was determined [33].
  • Overexpression of GM130 suppressed HERG current amplitude in Xenopus oocytes, as if by providing an excess of substrate at the Golgi checkpoint [29].
  • HERG was expressed in Xenopus oocytes with or without additional expression of SGK1 or SGK3 [34].

Other interactions of KCNH2

  • The risk of cardiac events is significantly higher among subjects with mutations at the LQT1 or LQT2 locus than among those with mutations at the LQT3 locus [9].
  • KCNQ1 and HERG appear to share unique interactions with KCNE1, 2 and 3 subunits [35].
  • So far, KCNE2 (MirP1) has only been shown to modulate HERG current [35].
  • KCNE3 markedly changes KCNQ1 as well as HERG current properties [35].
  • Further genetic screening revealed that one A341V (KCNQ1) family cosegregated with S706C (KCNH2) and another with G144S (KCNJ2) [36].

Analytical, diagnostic and therapeutic context of KCNH2


  1. An intronic mutation causes long QT syndrome. Zhang, L., Vincent, G.M., Baralle, M., Baralle, F.E., Anson, B.D., Benson, D.W., Whiting, B., Timothy, K.W., Carlquist, J., January, C.T., Keating, M.T., Splawski, I. J. Am. Coll. Cardiol. (2004) [Pubmed]
  2. Role of a KCNH2 polymorphism (R1047 L) in dofetilide-induced Torsades de Pointes. Sun, Z., Milos, P.M., Thompson, J.F., Lloyd, D.B., Mank-Seymour, A., Richmond, J., Cordes, J.S., Zhou, J. J. Mol. Cell. Cardiol. (2004) [Pubmed]
  3. Short QT syndrome and atrial fibrillation caused by mutation in KCNH2. Hong, K., Bjerregaard, P., Gussak, I., Brugada, R. J. Cardiovasc. Electrophysiol. (2005) [Pubmed]
  4. Sudden death associated with short-QT syndrome linked to mutations in HERG. Brugada, R., Hong, K., Dumaine, R., Cordeiro, J., Gaita, F., Borggrefe, M., Menendez, T.M., Brugada, J., Pollevick, G.D., Wolpert, C., Burashnikov, E., Matsuo, K., Wu, Y.S., Guerchicoff, A., Bianchi, F., Giustetto, C., Schimpf, R., Brugada, P., Antzelevitch, C. Circulation (2004) [Pubmed]
  5. Human ether-a-go-go related gene (hERG) K+ channels: function and dysfunction. Perrin, M.J., Subbiah, R.N., Vandenberg, J.I., Hill, A.P. Prog. Biophys. Mol. Biol. (2008) [Pubmed]
  6. Regulation of HERG potassium channel activation by protein kinase C independent of direct phosphorylation of the channel protein. Thomas, D., Zhang, W., Wu, K., Wimmer, A.B., Gut, B., Wendt-Nordahl, G., Kathöfer, S., Kreye, V.A., Katus, H.A., Schoels, W., Kiehn, J., Karle, C.A. Cardiovasc. Res. (2003) [Pubmed]
  7. Interactions of the narcotic l-alpha-acetylmethadol with human cardiac K+ channels. Kang, J., Chen, X.L., Wang, H., Rampe, D. Eur. J. Pharmacol. (2003) [Pubmed]
  8. MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia. Abbott, G.W., Sesti, F., Splawski, I., Buck, M.E., Lehmann, M.H., Timothy, K.W., Keating, M.T., Goldstein, S.A. Cell (1999) [Pubmed]
  9. Influence of genotype on the clinical course of the long-QT syndrome. International Long-QT Syndrome Registry Research Group. Zareba, W., Moss, A.J., Schwartz, P.J., Vincent, G.M., Robinson, J.L., Priori, S.G., Benhorin, J., Locati, E.H., Towbin, J.A., Keating, M.T., Lehmann, M.H., Hall, W.J. N. Engl. J. Med. (1998) [Pubmed]
  10. Crystal structure and functional analysis of the HERG potassium channel N terminus: a eukaryotic PAS domain. Morais Cabral, J.H., Lee, A., Cohen, S.L., Chait, B.T., Li, M., Mackinnon, R. Cell (1998) [Pubmed]
  11. Short QT syndrome. Genotype-phenotype correlations. Borggrefe, M., Wolpert, C., Antzelevitch, C., Veltmann, C., Giustetto, C., Gaita, F., Schimpf, R. Journal of electrocardiology. (2005) [Pubmed]
  12. Mutations in the HERG K+-ion channel: a novel link between long QT syndrome and sudden infant death syndrome. Christiansen, M., Tønder, N., Larsen, L.A., Andersen, P.S., Simonsen, H., Oyen, N., Kanters, J.K., Jacobsen, J.R., Fosdal, I., Wettrell, G., Kjeldsen, K. Am. J. Cardiol. (2005) [Pubmed]
  13. A novel mutation (T65P) in the PAS domain of the human potassium channel HERG results in the long QT syndrome by trafficking deficiency. Paulussen, A., Raes, A., Matthijs, G., Snyders, D.J., Cohen, N., Aerssens, J. J. Biol. Chem. (2002) [Pubmed]
  14. Differential effects of beta-blockade on dispersion of repolarization in the absence and presence of sympathetic stimulation between the LQT1 and LQT2 forms of congenital long QT syndrome. Shimizu, W., Tanabe, Y., Aiba, T., Inagaki, M., Kurita, T., Suyama, K., Nagaya, N., Taguchi, A., Aihara, N., Sunagawa, K., Nakamura, K., Ohe, T., Towbin, J.A., Priori, S.G., Kamakura, S. J. Am. Coll. Cardiol. (2002) [Pubmed]
  15. The antihistamine fexofenadine does not affect I(Kr) currents in a case report of drug-induced cardiac arrhythmia. Scherer, C.R., Lerche, C., Decher, N., Dennis, A.T., Maier, P., Ficker, E., Busch, A.E., Wollnik, B., Steinmeyer, K. Br. J. Pharmacol. (2002) [Pubmed]
  16. Downregulation of the HERG (KCNH2) K(+) channel by ceramide: evidence for ubiquitin-mediated lysosomal degradation. Chapman, H., Ramström, C., Korhonen, L., Laine, M., Wann, K.T., Lindholm, D., Pasternack, M., Törnquist, K. J. Cell. Sci. (2005) [Pubmed]
  17. Functional characterization of the common amino acid 897 polymorphism of the cardiac potassium channel KCNH2 (HERG). Paavonen, K.J., Chapman, H., Laitinen, P.J., Fodstad, H., Piippo, K., Swan, H., Toivonen, L., Viitasalo, M., Kontula, K., Pasternack, M. Cardiovasc. Res. (2003) [Pubmed]
  18. 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. Larsen, L.A., Andersen, P.S., Kanters, J., Svendsen, I.H., Jacobsen, J.R., Vuust, J., Wettrell, G., Tranebjaerg, L., Bathen, J., Christiansen, M. Clin. Chem. (2001) [Pubmed]
  19. Gastrointestinal symptoms in families of patients with an SCN5A-encoded cardiac channelopathy: evidence of an intestinal channelopathy. Locke, G.R., Ackerman, M.J., Zinsmeister, A.R., Thapa, P., Farrugia, G. Am. J. Gastroenterol. (2006) [Pubmed]
  20. Expression and function of KCNH2 (HERG) in the human jejunum. Farrelly, A.M., Ro, S., Callaghan, B.P., Khoyi, M.A., Fleming, N., Horowitz, B., Sanders, K.M., Keef, K.D. Am. J. Physiol. Gastrointest. Liver Physiol. (2003) [Pubmed]
  21. Analysis of the human KCNH2(HERG) gene: identification and characterization of a novel mutation Y667X associated with long QT syndrome and a non-pathological 9 bp insertion. Paulussen, A., Yang, P., Pangalos, M., Verhasselt, P., Marrannes, R., Verfaille, C., Vandenberk, I., Crabbe, R., Konings, F., Luyten, W., Armstrong, M. Hum. Mutat. (2000) [Pubmed]
  22. Species diversity and peptide toxins blocking selectivity of ether-a-go-go-related gene subfamily K+ channels in the central nervous system. Restano-Cassulini, R., Korolkova, Y.V., Diochot, S., Gurrola, G., Guasti, L., Possani, L.D., Lazdunski, M., Grishin, E.V., Arcangeli, A., Wanke, E. Mol. Pharmacol. (2006) [Pubmed]
  23. Identification and functional characterization of a novel KCNE2 (MiRP1) mutation that alters HERG channel kinetics. Isbrandt, D., Friederich, P., Solth, A., Haverkamp, W., Ebneth, A., Borggrefe, M., Funke, H., Sauter, K., Breithardt, G., Pongs, O., Schulze-Bahr, E. J. Mol. Med. (2002) [Pubmed]
  24. Inhibition of cardiac delayed rectifier K+ currents by an antisense oligodeoxynucleotide against IsK (minK) and over-expression of IsK mutant D77N in neonatal mouse hearts. Ohyama, H., Kajita, H., Omori, K., Takumi, T., Hiramoto, N., Iwasaka, T., Matsuda, H. Pflugers Arch. (2001) [Pubmed]
  25. Long QT syndrome with a high mortality rate caused by a novel G572R missense mutation in KCNH2. Larsen, L.A., Svendsen, I.H., Jensen, A.M., Kanters, J.K., Andersen, P.S., Møller, M., Sørensen, S.A., Sandøe, E., Jacobsen, J.R., Vuust, J., Christiansen, M. Clin. Genet. (2000) [Pubmed]
  26. Cyclic AMP regulates the HERG K(+) channel by dual pathways. Cui, J., Melman, Y., Palma, E., Fishman, G.I., McDonald, T.V. Curr. Biol. (2000) [Pubmed]
  27. Modulation of rat erg1, erg2, erg3 and HERG K+ currents by thyrotropin-releasing hormone in anterior pituitary cells via the native signal cascade. Schledermann, W., Wulfsen, I., Schwarz, J.R., Bauer, C.K. J. Physiol. (Lond.) (2001) [Pubmed]
  28. Molecular and functional characterization of common polymorphisms in HERG (KCNH2) potassium channels. Anson, B.D., Ackerman, M.J., Tester, D.J., Will, M.L., Delisle, B.P., Anderson, C.L., January, C.T. Am. J. Physiol. Heart Circ. Physiol. (2004) [Pubmed]
  29. Interaction with GM130 during HERG ion channel trafficking. Disruption by type 2 congenital long QT syndrome mutations. Human Ether-à-go-go-Related Gene. Roti, E.C., Myers, C.D., Ayers, R.A., Boatman, D.E., Delfosse, S.A., Chan, E.K., Ackerman, M.J., January, C.T., Robertson, G.A. J. Biol. Chem. (2002) [Pubmed]
  30. Co-chaperone FKBP38 promotes HERG trafficking. Walker, V.E., Atanasiu, R., Lam, H., Shrier, A. J. Biol. Chem. (2007) [Pubmed]
  31. Correlation of genetic etiology with response to beta-adrenergic blockade among symptomatic patients with familial long-QT syndrome. Itoh, T., Kikuchi, K., Odagawa, Y., Takata, S., Yano, K., Okada, S., Haneda, N., Ogawa, S., Nakano, O., Kawahara, Y., Kasai, H., Nakayama, T., Fukutomi, T., Sakurada, H., Shimizu, A., Yazaki, Y., Nagai, R., Nakamura, Y., Tanaka, T. J. Hum. Genet. (2001) [Pubmed]
  32. Normal function of HERG K+ channels expressed in HEK293 cells requires basal protein kinase B activity. Zhang, Y., Wang, H., Wang, J., Han, H., Nattel, S., Wang, Z. FEBS Lett. (2003) [Pubmed]
  33. Effect of beta-adrenoceptor blockers on human ether-a-go-go-related gene (HERG) potassium channels. Dupuis, D.S., Klaerke, D.A., Olesen, S.P. Basic & clinical pharmacology & toxicology. (2005) [Pubmed]
  34. Upregulation of HERG Channels by the Serum and Glucocorticoid Inducible Kinase Isoform SGK3. Maier, G., Palmada, M., Rajamanickam, J., Shumilina, E., Bohmer, C., Lang, F. Cell. Physiol. Biochem. (2006) [Pubmed]
  35. KCNE2 confers background current characteristics to the cardiac KCNQ1 potassium channel. Tinel, N., Diochot, S., Borsotto, M., Lazdunski, M., Barhanin, J. EMBO J. (2000) [Pubmed]
  36. Additional gene variants reduce effectiveness of beta-blockers in the LQT1 form of long QT syndrome. Kobori, A., Sarai, N., Shimizu, W., Nakamura, Y., Murakami, Y., Makiyama, T., Ohno, S., Takenaka, K., Ninomiya, T., Fujiwara, Y., Matsuoka, S., Takano, M., Noma, A., Kita, T., Horie, M. J. Cardiovasc. Electrophysiol. (2004) [Pubmed]
  37. A molecular basis for cardiac arrhythmia: HERG mutations cause long QT syndrome. Curran, M.E., Splawski, I., Timothy, K.W., Vincent, G.M., Green, E.D., Keating, M.T. Cell (1995) [Pubmed]
  38. Postmortem molecular screening in unexplained sudden death. Chugh, S.S., Senashova, O., Watts, A., Tran, P.T., Zhou, Z., Gong, Q., Titus, J.L., Hayflick, S.J. J. Am. Coll. Cardiol. (2004) [Pubmed]
  39. HERG K(+) currents in human prolactin-secreting adenoma cells. Bauer, C.K., Wulfsen, I., Schäfer, R., Glassmeier, G., Wimmers, S., Flitsch, J., Lüdecke, D.K., Schwarz, J.R. Pflugers Arch. (2003) [Pubmed]
  40. Sinus node function and ventricular repolarization during exercise stress test in long QT syndrome patients with KvLQT1 and HERG potassium channel defects. Swan, H., Viitasalo, M., Piippo, K., Laitinen, P., Kontula, K., Toivonen, L. J. Am. Coll. Cardiol. (1999) [Pubmed]
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