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KCNH2 gene

potassium voltage-gated channel subfamily H member 2
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Normal Function

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.

Health Conditions Related to Genetic Changes

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.

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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.

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Familial atrial fibrillation

MedlinePlus Genetics provides information about Familial atrial fibrillation

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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.

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

Additional Information & Resources

Tests Listed in the Genetic Testing Registry

Scientific Articles on PubMed

Catalog of Genes and Diseases from OMIM

Research Resources

References

  • Alders M, Bikker H, Christiaans I. Long QT Syndrome. 2003 Feb 20 [updated 2018 Feb 8]. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, Bean LJH, Stephens K, Amemiya A, editors. GeneReviews┬« [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020. Available from http://www.ncbi.nlm.nih.gov/books/NBK1129/ Citation on PubMed
  • Brugada R, Hong K, Dumaine R, Cordeiro J, Gaita F, Borggrefe M, Menendez TM, Brugada J, Pollevick GD, Wolpert C, Burashnikov E, Matsuo K, Wu YS, Guerchicoff A, Bianchi F, Giustetto C, Schimpf R, Brugada P, Antzelevitch C. Sudden death associated with short-QT syndrome linked to mutations in HERG. Circulation. 2004 Jan 6;109(1):30-5. Epub 2003 Dec 15. Citation on PubMed
  • 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 QT syndrome. Cardiovasc Res. 2005 Aug 15;67(3):498-509. Epub 2005 Mar 28. Citation on PubMed
  • Hong K, Bjerregaard P, Gussak I, Brugada R. Short QT syndrome and atrial fibrillation caused by mutation in KCNH2. J Cardiovasc Electrophysiol. 2005 Apr;16(4):394-6. Citation on PubMed
  • 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 voltage sensor. J Membr Biol. 2013 May;246(5):355-64. doi: 10.1007/s00232-013-9539-6. Epub 2013 Apr 2. Citation on PubMed or Free article on PubMed Central
  • Paulussen AD, Gilissen RA, Armstrong M, Doevendans PA, Verhasselt P, Smeets HJ, Schulze-Bahr E, Haverkamp W, Breithardt G, Cohen N, Aerssens J. Genetic variations of KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 in drug-induced long QT syndrome patients. J Mol Med (Berl). 2004 Mar;82(3):182-8. Epub 2004 Feb 4. Citation on PubMed
  • 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 but causes long QT by heterotetrameric trafficking deficiency. Cardiovasc Res. 2005 Aug 15;67(3):467-75. Citation on PubMed
  • Sanguinetti MC. HERG1 channelopathies. Pflugers Arch. 2010 Jul;460(2):265-76. doi: 10.1007/s00424-009-0758-8. Epub 2009 Nov 22. Review. Citation on PubMed or Free article on PubMed Central
  • Schimpf R, Wolpert C, Gaita F, Giustetto C, Borggrefe M. Short QT syndrome. Cardiovasc Res. 2005 Aug 15;67(3):357-66. Review. Citation on PubMed
  • Smith JL, Anderson CL, Burgess DE, Elayi CS, January CT, Delisle BP. Molecular pathogenesis of long QT syndrome type 2. J Arrhythm. 2016 Oct;32(5):373-380. Epub 2016 Jan 22. Review. Citation on PubMed or Free article on PubMed Central
  • 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 QT syndrome. J Mol Cell Cardiol. 2011 Mar;50(3):433-41. doi: 10.1016/j.yjmcc.2010.11.017. Epub 2010 Dec 3. Citation on PubMed
  • Thomas D, Kiehn J, Katus HA, Karle CA. Defective protein trafficking in hERG-associated hereditary long QT syndrome (LQT2): molecular mechanisms and restoration of intracellular protein processing. Cardiovasc Res. 2003 Nov 1;60(2):235-41. Review. Citation on PubMed
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