Gene:

KCNH2

potassium voltage-gated channel, subfamily H (eag-related), member 2

Overview

Details

Introduction

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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.

Curated Annotations ()

1. rs3815459 at chr7:150275327 in KCNH2
   Associated with the QT interval; the A allele is more common with long QT.

   Variant Name:

   KCNH2:rs3815459

   Evidence:

   PMID:15746444
   PMID:17534376
   

2. rs36210421 at chr7:150275361 in KCNH2
   Results of in vitro assays from this study suggest that the R1047L polymorphism leads to a functional impairment of the channel, which may contribute to the higher incidence of Torsades de Pointes in 1047L carriers when challenged with a channel blocker.

   Variant Name:

   KCNH2: R1047L

   Related Drugs:

   dofetilide

   Related Diseases:

   Torsades de Pointes

   Evidence:

   PMID:15522280
   

3. rs36210421 at chr7:150275361 in KCNH2
   in vitro studies showed cisapride has same sensitivity for WT and this varian

   Variant Name:

   R1047L

   Related Diseases:

   Acquired Long QT Syndrome (aLQTS), Long QT Syndrome

   Evidence:

   PMID:14975928
   

4. rs1805123 at chr7:150276467 in KCNH2
   Associated with QT interval duration.

   Variant Name:

   KCNH2:K897T

   Evidence:

   PMID:15746444
   PMID:17709632
   

5. rs1805123 at chr7:150276467 in KCNH2
   Altered biophysics; creates phosphorylation site that inhibits channel

   Variant Name:

   K897T

   Related Diseases:

   Acquired Long QT Syndrome (aLQTS), Long QT Syndrome

   Evidence:

   PMID:14975928
   PMID:18791070
   

6. rs1805123 at chr7:150276467 in KCNH2
   shortened QT interval

   Variant Name:

   K897T

   Evidence:

   PMID:12829173
   PMID:19019189
   

7. rs1805123 at chr7:150276467 in KCNH2
   associated with higher incidence of atrial fibrillation

   Variant Name:

   K897T

   Evidence:

   PMID:18222980
   

8. rs12720441 at chr7:150278237 in KCNH2
   Mutation may be responsible for response to amiodarone

   Variant Name:

   R784W

   Related Drugs:

   amiodarone

   Evidence:

   PMID:11997281
   

9. rs3807375 at chr7:150298143 in KCNH2
   Associated with QT interval duration.

   Variant Name:

   KCNH2:rs3807375

   Evidence:

   PMID:17709632
   

10. rs3807375 at chr7:150298143 in KCNH2
    QT prolongation

    Evidence:

    PMID:19019189
    

Curated Information

The following genes are in curated knowledge about this gene.

	Gene	Relationship	Evidence
	ALG10B	FA	Publications

Non-Curated Information

A list of non-curated publications that mention this gene along with other genes is available.

PharmGKB Curated Pathways

• Antiarrhythmic Drug Pathway

Curated Information

The following drugs are in curated knowledge about this gene.

	Drug Class	Relationship	Evidence
	antiarrhythmics, class i and iii	CO       FA GN	Publications
	Beta blocking agents, selective	CO          GN	Publications

	Drug	Relationship	Evidence
	amiodarone	GN	Publications, Variants
	arsenic trioxide	PD    FA	Publications
	astemizole	CO PD    FA	Publications
	chlorpheniramine	PD    FA	Publications
	cimetidine	PD    FA	Publications
	cisapride	CO PD    FA GN	Publications
	clarithromycin	FA GN	Publications
	disopyramide	PD    FA	Publications
	dofetilide	PD    FA GN	Publications, Variants
	doxepin	PD    FA	Publications
	droperidol	PD    FA	Publications
	erythromycin	PD    FA	Publications
	fluoxetine	PD	Publications
	fluvoxamine	PD	Publications
	grepafloxacin	CO PD    FA	Publications
	haloperidol	PD    FA	Publications
	hydroxyzine		Publications
	ibutilide	PD    FA	Publications
	levomethadyl acetate	PD    FA	Publications
	loratadine	PD    FA	Publications
	lovastatin	PD    FA	Publications
	methadone	PD PK    GN	Publications
	mexiletine	PD	Publications
	mibefradil	PD    FA	Publications
	moxifloxacin	PD PK FA	Publications
	olanzapine	PD    FA	Publications
	pentamidine	PD    FA	Publications
	perhexiline	FA	Publications
	pimozide	PD    FA	Publications
	probucol	PD    FA GN	Publications
	procainamide	PD    FA	Publications
	quetiapine	PD    FA	Publications
	quinidine	CO PD    FA	Publications
	risperidone	PD    FA	Publications
	sertindole	CO PD    FA	Publications
	silodosin	PD PK	Publications
	sotalol	PD    FA GN	Publications
	sparfloxacin	PD    FA	Publications
	telithromycin	PD    FA	Publications
	terfenadine	CO PD    FA	Publications
	thioridazine	PD    FA	Publications
	trazodone	PD	Publications
	warfarin	CO          GN	Publications
	ziprasidone	PD    FA	Publications

Non-Curated Information

A list of non-curated publications that mention this gene along with other drugs is available.

Curated Information

The following diseases are in curated knowledge about this gene.

	Disease	Relationship	Evidence
	Abnormalities, Drug-Induced	GN	Publications
	Acquired Long QT Syndrome (aLQTS)	CO PD    FA GN	Publications, Variants
	Arrhythmias, Cardiac	CO          GN	Publications
	Atrial Fibrillation	CO          GN	Publications
	Brugada syndrome	CO          GN	Publications
	Cardiomyopathy, Hypertrophic	CO          GN	Publications
	congenital long QT syndrome	GN	Publications
	Coronary Artery Disease	CO          GN	Publications
	Coronary Disease	CO          GN	Publications
	Death, Sudden, Cardiac	CO          GN	Publications
	Heart Diseases	CO          GN	Publications
	Long QT Syndrome	CO PD    FA GN	Publications, Variants
	Myocardial Infarction	CO          GN	Publications
	Sudden Infant Death	CO          GN	Publications
	Tachycardia, Ventricular	PD PK	Publications
	Thromboembolism	CO          GN	Publications
	Torsades de Pointes	CO PD    FA GN	Publications, Variants
	Ventricular Fibrillation	CO          GN	Publications

Non-Curated Information

A list of non-curated publications that mention this gene along with other diseases is available.

Curated Phenotype Datasets

These datasets are sorted alphabetically by title.

1. A modulator of HERG Potassium Channel block

   • 
   • 
   • 
   • 
   • FA

   Submitted by Dan Roden, MD involving ALG10, KCNH2, dofetilide, qt-prolonging drugs, and Torsades de Pointes
2. Drug-Induced Long QT Intervals

   • 
   • 
   • 
   • 
   • PD

   Submitted by Dan Roden, MD involving ADRB1, ADRB2, KCNE1, KCNE2, KCNH2, KCNQ1, SCN5A, almokalant, amiodarone, amitriptyline, bretylium, bupivacaine, cisapride, disopyramide, dofetilide, encainide, fluconazole, haloperidol, hydroquinidine, isoflurane, itraconazole, ketoconazole, lithium, loratadine, metoclopramide, nortriptyline, procainamide, quinidine, sematilide, sotalol, sulfamethoxazole, thioridazine, trimethoprim, , Long QT Syndrome, Proarrhythmia and Torsades de Pointes

Additional Datasets

These datasets are minimally curated and are sorted alphabetically by title.

1. A chemogenomic approach to drug discovery: focus on cardiovascular diseases
2. Genetic Associations in Drug-induced QT Prolongation and Torsades

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LinkOuts

Common Searches

• Comparative Genomics at UCSC
• Search BioCarta and KEGG Pathways at CGAP
• Search Reactome

Non-Curated Publications

A list of non-curated publications that mention this gene is available.