Annotated PGx Gene Information for KCNH2
Citation: KCNH2 pharmacogenomics summary. Oshiro C, Thorn CF, Roden DM, Klein TE, Altman RB. Pharmacogenet Genomics. 2010 Feb 10.
Epub ahead of print. PMID:20150828
Submitted by: Connie Oshiro, Caroline Thorn
Reviewed by: Dan Roden (PAT)
Submitted date: June 2009
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| Gene HGNC Name: | KCNH2 |
|---|---|
| Gene Common Name: | hERG; human ether-a-go-go-related potassium channel |
| Introductory Information: | The KCNH2 gene, or human Ether-a-go-go Related Gene (hERG), codes for a potassium voltage gated ion channel [PMID:14999113,7736582]. The current through the channel is termed the rapid component of the cardiac delayed rectifier (I Kr). The gene is located on chromosome 7 and has 15 exons. Mutations and variants of KCNH2 are one cause of the congenital long QT syndrome (LQTS), a rare syndrome that carries an increased risk of cardiac arrhythmias, including the polymorphic ventricular tachycardia termed torsades de pointes (TdP), which can be fatal [PMID:17143043, 16554806 ]. There has also been an association between KCNH2 variants and sudden infant death syndrome (SIDS) [PMID:947572 ]. Variants in many other genes can cause congenital LQTS (see, for example, OMIM KCNQ1 , OMIM KCNE2 , and OMIM SCN5A ). However, the syndrome of drug-induced LQTS is most often caused by the block of the hERG channels encoded by the KCNH2 gene.[PMID:18447395, 17143043, 16554806, 12747773, 7736582]. Other mechanism for drug-associated QT prolongation and Tdp have been reported [PMID:18447395, 8873679]. In addition, other conditions, such as heart block or severe electrolyte abnormalities, can also cause QT prolongation and TdP; collectively, the drug-induced and other forms are termed the acquired LQTS (aLQTS). For the remainder of this summary, the gene KCNH2 and the encoded protein, hERG, will be used interchangeably. There are more than 100 reported mutations of the KCNH2 gene related to congenital LQTS. See, for example, external websites: OMIM KCNH2 , connections for heart hERG polymorphisms , connections for heart hERG mutations , LQTS db hERG mutations . In addition, gene deletions and duplications have been seen in patients with congenital LQTS [PMID:18774102,16399053 ]. However, there are very few variants and amino acid changes have been clearly associated with drug-induced hERG-related LQTS. For example, K897T (rs1805123) has been shown, in several studies, to be associated with longer [PMID:15746444, 14499861],or shorter QT intervals [PMID: 10862094, 12829173, 19019189]. K897T was also shown to create a phosphorylation site that inhibited channel activity, independent of drug binding [PMID:18791070]. But, the impact of common KCNH2 polymorphisms, including K897T as well as P967L, R1047L (rs36210421) and Q1068R were found to have no significant differences in cisapride IC50 values or Hill coefficients (compared to wild-type) for inhibition of the encoded current by the prototypical blocker cisapride [PMID:14975928]. A number of studies have strongly supported the idea that variation not only in KCNH2 but also in other cardiac ion channel and associated genes may predispose to aLQTS. Yang et al [PMID:11997281] found that approximately 5% to 10% of individuals with drug-induced TdP actually may have congenital LQTS with rare LQTS-associated channel mutations. This study also identified R784W (rs12720441 ) in patients with drug-associated (amiodarone) TdP [PMID:11997281]. In addition, Kannankeril, et al [PMID:15851285] found that quinidine prolongs terminal repolarization in family members of patients with drug-induced long QT syndrome, but not in family members of patients who safely tolerate chronic therapy with QT-prolonging drugs Virtually all drugs that cause drug-induced QT prolongation are KCNH2/I Kr blockers [PMID:12747773, 16554806]. Eight drugs (astemizole, sertindole, terfenadine, cisapride, grepafloxacin, terodiline, lidoflazine, levomethadyl) have been removed from the market because of the risk of aLQTS and fatal TdP [PMID:15718164, 14999113]; and a ninth, droperidol, has received highly restrictive labeling [PMID:14999113]. As a result of these events, testing for hERG blocking activity and subsequent evaluations for QT interval prolonging potential are routine in the pharmaceutical industry and such screening has resulted in the halting of drug development of compounds that exhibit these potentially undesirable effects. [PMID:11166255, 16554806] The list of QT-prolonging drugs and hERG/I Kr inhibitors is large and diverse. See below under Drugs/Substrates. |
| Key PubMed IDs: | 11997281, 14999113, 16554806,17143043,18447395,11005845, 14975928 7736582 |
| Key Pathways: | Antiarrhythmic Drug Pathways |
| Drugs/Substrates: | QT-prolonging drugs: Arizona CERT list of QT-related drugs (may or may not be hERG-related), Swiss Association hERG list of QT-related drugs Inhibitors of hERG/I Kr amiodarone [PMID:11997281]; astemizole [PMID:15090000, 10376921, 14999113, 15718164, 16253929] and its metabolite desmethylastemizole [PMID:10376921]; cisapride [PMID:18987434, 15090000, 9374794, 14999113, 15718164, 16253929], disopyramide [PMID:14624285]; dofetilide[PMID:15522280, 11698075]; erythromycin[PMID:16614168, 18701618] ; fluoxetine [PMID:11805215]; grepafloxacin [PMID:15090000, 14999113, 15718164, 16253929]; haloperidol IC50~63nM [PMID:16278312]; hydroxyzine[PMID:19057127]; ibutilide [PMID:14624285]; levomethadyl [PMID:14999113, 16253929]; lidoflazine IC50<37nM [PMID:16278312, 14999113]; methadone [PMID:17329992]; mibefradil [PMID:16253929]; moxifloxacin [PMID:16614168]; perhexiline [PMID:18701618] ; pimozide IC50~18nM [PMID:12176106]; prenylamine IC50~590nM [PMID:16278312] ; probucol [PMID:15043509] ; quinidine [PMID:14624285, 18701618]; risperidone IC50 ~167nM [PMID:12176106]; sertindole IC50~3nM [PMID:12176106], IC50~210nM [PMID:16278312]; sotalol [PMID:14624285, 18701618]; telithromycin [PMID:16614168]; terfenadine IC50<52nM [PMID:16278312], [PMID:18987434, 15090000, 14999113, 16253929]; terodiline [PMID:15090000, 14999113, 15718164]; thioridazine IC50~191nM [PMID:12176106], IC50~224nM [PMID:16051556]; ziprasidone IC50~169nM [PMID:12176106] Weak inhibitors of hERG/I Kr (IC50>1uM) arsenic trioxide I Kr ~300uM [PMID:16278312]; chlorpheniramine IC50~13uM [PMID:16278312]; cimetidine IC50>10uM [PMID:16278312]; doxepin IC50~4uM [PMID:17560554]; loratadine IC50~4uM [PMID:16278312]; lovastatin IC50~7uM [PMID:16278312]; olanzapine IC50~6013 nM [PMID:12176106]; pentamidine Iherg~1mM [PMID:16278312]; procainamide IC50~139 uM [PMID:12804575]; pyrilamine IC50~6uM [PMID:16278312]; quetiapine IC50~5765 nM [PMID:12176106]; sparfloxacin (fluoroquinolone) IC50 ~18 uM [PMID:11125032,12176106] drugs that prolong QT interval by reducing cell surface KCNH2 expression: pentamidine [PMID:15711592]; arsenic trioxide [PMID:15213294]. |
| Phenotypes/Diseases: | LQTS, drug-induced (acquired) LQTS, congenital LQTS , Torsades de Pointes , Ventricular tachycardia , short QT syndrome (SQTS) OMIM SQTS , Atrial Fibrillation |
| Phenotype datasets: | A modulator of HERG Potassium Channel block, Drug-Induced Long QT Intervals |
| Structural information: | Amino acids Y652 and F656 in the pore region of the channel are important for the binding of drugs/inhibitors [PMID:18987434, 15266014, 11005845] |
| Important Variants: | KCNH2:K897T, 1670A>C , KCNH2:R784W, 1330C>T , KCNH2:R1047L, 2120G>T KCNH2: 11220410 C>T KCNH2: 11243226 C>T |
| Important Haplotypes: | KCNH2 haplotypes have been reported to modulate variability in the QT interval in population studies [PMID: 19305409, 15746444, 19305408] |
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