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    KCNH2 Gene

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    Submitted by: Dean Liu
    (This entry belongs to Entry Collection "MedlinePlus ")

    Definition

    Potassium voltage-gated channel subfamily H member 2

    1. Introduction

    The KCNH2 gene belongs to a large family of genes that provide instructions for making potassium channels. These channels, which transport positively charged atoms (ions) of potassium out of cells, play key roles in a cell's ability to generate and transmit electrical signals.

    The specific function of a potassium channel depends on its protein components and its location in the body. Channels made with KCNH2 proteins (also known as hERG1) are active in heart (cardiac) muscle. They are involved in recharging the cardiac muscle after each heartbeat to maintain a regular rhythm. The KCNH2 protein is also produced in nerve cells and certain immune cells (microglia) in the brain and spinal cord (central nervous system).

    The proteins produced from the KCNH2 gene and another gene, KCNE2, interact to form a functional potassium channel. Four alpha subunits, each produced from the KCNH2 gene, form the structure of each channel. One beta subunit, produced from the KCNE2 gene, attaches (binds) to the channel and regulates its activity.

    2. Health Conditions Related to Genetic Changes

    2.1. Romano-Ward Syndrome

    Mutations in the KCNH2 gene can cause Romano-Ward syndrome, which is the most common form of a heart condition called long QT syndrome. Mutations in this gene account for approximately 25 percent of cases of Romano-Ward syndrome. In individuals with this condition, the heart muscle takes longer than usual to recharge between beats, which can lead to an abnormal heart rhythm (arrhythmia).

    More than 900 KCNH2 gene mutations that cause Romano-Ward syndrome have been identified. Some of these mutations change single protein building blocks (amino acids) in the KCNH2 protein, while other mutations delete several amino acids from the protein. These changes prevent the protein from assembling into ion channels or alter the channels' structure or function. As a result, the channels cannot properly regulate the flow of potassium ions in cardiac muscle cells. The reduced ion transport alters the transmission of electrical signals in the heart, increasing the risk of an irregular heartbeat that can cause fainting (syncope) or sudden death.

    2.2. Short QT Syndrome

    Mutations in the KCNH2 gene can also cause a heart condition called short QT syndrome. In people with this condition, the cardiac muscle takes less time than usual to recharge between beats. This change increases the risk of an abnormal heart rhythm that can cause syncope or sudden death.

    At least eight mutations in the KCNH2 gene have been found to cause short QT syndrome in a small number of affected families. These mutations change single amino acids in the KCNH2 protein. The genetic changes alter the function of ion channels made with the KCNH2 protein, increasing the channels' activity. As a result, more potassium ions flow out of cardiac muscle cells at a critical time during the heartbeat, which can lead to an irregular heart rhythm.

    2.3. Other Disorders

    Certain drugs, including medications used to treat arrhythmias, infections, seizures, psychiatric disorders, and other problems can lead to an abnormal heart rhythm in some people. This drug-induced heart condition, which is known as acquired long QT syndrome, increases the risk of cardiac arrest and sudden death. A small percentage of cases of acquired long QT syndrome occur in people who have an underlying variation in the KCNH2 gene.

    3. Other Names for This Gene

    • ERG1

    • ether-a-go-go related gene potassium channel 1

    • H-ERG

    • HERG

    • HERG1

    • human ether a-go-go-related gene

    • KCNH2_HUMAN

    • Kv11.1

    • LQT2

    • potassium channel, voltage gated eag related subfamily H, member 2

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

    This entry is adapted from https://medlineplus.gov/genetics/gene/kcnh2

    References

    1. Alders M, Bikker H, Christiaans I. Long QT Syndrome. 2003 Feb 20 [updated 2018Feb 8]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K,Amemiya A, editors. GeneReviews® [Internet]. Seattle (WA): University ofWashington, Seattle; 1993-2020. Available fromhttp://www.ncbi.nlm.nih.gov/books/NBK1129/
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    3. Cordeiro JM, Brugada R, Wu YS, Hong K, Dumaine R. Modulation of I(Kr)inactivation by mutation N588K in KCNH2: a link to arrhythmogenesis in short QTsyndrome. Cardiovasc Res. 2005 Aug 15;67(3):498-509.
    4. Hong K, Bjerregaard P, Gussak I, Brugada R. Short QT syndrome and atrialfibrillation caused by mutation in KCNH2. J Cardiovasc Electrophysiol. 2005Apr;16(4):394-6.
    5. McBride CM, Smith AM, Smith JL, Reloj AR, Velasco EJ, Powell J, Elayi CS,Bartos DC, Burgess DE, Delisle BP. Mechanistic basis for type 2 long QT syndrome caused by KCNH2 mutations that disrupt conserved arginine residues in the voltagesensor. J Membr Biol. 2013 May;246(5):355-64. doi: 10.1007/s00232-013-9539-6.
    6. Paulussen AD, Gilissen RA, Armstrong M, Doevendans PA, Verhasselt P, SmeetsHJ, Schulze-Bahr E, Haverkamp W, Breithardt G, Cohen N, Aerssens J. Geneticvariations of KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 in drug-induced long QTsyndrome patients. J Mol Med (Berl). 2004 Mar;82(3):182-8.
    7. Paulussen AD, Raes A, Jongbloed RJ, Gilissen RA, Wilde AA, Snyders DJ, Smeets HJ, Aerssens J. HERG mutation predicts short QT based on channel kinetics butcauses long QT by heterotetrameric trafficking deficiency. Cardiovasc Res. 2005Aug 15;67(3):467-75.
    8. Sanguinetti MC. HERG1 channelopathies. Pflugers Arch. 2010 Jul;460(2):265-76. doi: 10.1007/s00424-009-0758-8.
    9. Schimpf R, Wolpert C, Gaita F, Giustetto C, Borggrefe M. Short QT syndrome.Cardiovasc Res. 2005 Aug 15;67(3):357-66. Review.
    10. Smith JL, Anderson CL, Burgess DE, Elayi CS, January CT, Delisle BP. Molecularpathogenesis of long QT syndrome type 2. J Arrhythm. 2016 Oct;32(5):373-380.
    11. Sun Y, Quan XQ, Fromme S, Cox RH, Zhang P, Zhang L, Guo D, Guo J, Patel C,Kowey PR, Yan GX. A novel mutation in the KCNH2 gene associated with short QTsyndrome. J Mol Cell Cardiol. 2011 Mar;50(3):433-41. doi:10.1016/j.yjmcc.2010.11.017.
    12. Thomas D, Kiehn J, Katus HA, Karle CA. Defective protein trafficking inhERG-associated hereditary long QT syndrome (LQT2): molecular mechanisms andrestoration of intracellular protein processing. Cardiovasc Res. 2003 Nov1;60(2):235-41. Review.
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