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KCNH2
potassium voltage-gated channel subfamily H member 2
The KCNH2 gene provides instructions for making a potassium channel protein crucial for regulating the electrical activity of heart muscle cells, maintaining a regular heart rhythm. KCNH2 encodes a primary subunit of the hERG potassium channel, which plays a pivotal role in the repolarisation phase of the cardiac action potential.
KCNH2 is located on the long (q) arm of chromosome 7, at band 7q36.1. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 7 in the library →Overview
The KCNH2 gene, also referred to as hERG1, provides the blueprint for a key protein component of potassium channels found within various human cells. These channels regulate cellular electrical activity by selectively transporting potassium ions, enabling the generation and propagation of electrical impulses [PMID:17965005]. While KCNH2-encoded proteins are present in nerve cells and specific immune cells in the brain, their most critical physiological role is in cardiac muscle, where they contribute significantly to the heart's electrical rhythm.
Potassium channels formed by KCNH2 proteins are essential for resetting the electrical charge of cardiac muscle cells between heartbeats, thereby supporting a consistent and regular rhythm [PMID:17965005]. Genetic changes in the KCNH2 gene can disrupt this delicate balance, leading to conditions characterised by abnormal heart rhythms, such as Long QT Syndrome and Short QT Syndrome.
What the gene does
The KCNH2 gene belongs to a large gene superfamily responsible for encoding potassium channels, which are transmembrane proteins that facilitate the movement of potassium ions. These channels are fundamental to cellular electrophysiology, influencing excitability across various tissues [PMID:17965005]. KCNH2 specifically encodes the alpha subunit (hERG) of a channel crucial for the delayed rectifier potassium current (IKr) in the heart. This current is vital for the repolarisation phase of the cardiac action potential, allowing the heart muscle to relax and prepare for its next contraction.
Each hERG channel typically consists of four KCNH2-derived alpha subunits, which together form the ion-conducting pore. A beta subunit, produced from the KCNE2 gene, can bind to this complex, modulating its response to voltage changes [PMID:17965005]. The precise behaviour of the channel can vary depending on the tissue context and the specific regulatory proteins present.
Within cardiac muscle cells, potassium channels involving KCNH2 proteins are responsible for controlling the duration of the action potential. This function prevents prolonged electrical activation and ensures the heart muscle can efficiently reset for subsequent contractions. Dysfunction in these channels can either prolong or shorten the action potential duration, leading to cardiac rhythm disorders. KCNH2 protein expression also occurs in the brain and spinal cord, where it is found in both neurons and specific immune cells called microglia. This suggests broader roles in electrical signalling and immune responses, although these functions are less comprehensively characterised than its cardiac role.
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Chromosome location
The KCNH2 gene is located on chromosome 7 at position 7q36.1. This precise genomic address indicates its presence on the long (q) arm of chromosome 7, within region 36, band 1. The gene covers a substantial segment of this chromosomal region, containing multiple exons that are transcribed and subsequently spliced to form the messenger RNA (mRNA), which then directs the synthesis of the KCNH2 protein. The gene's position on chromosome 7 is consistent across various human genome annotations.
Protein structure
The KCNH2 protein, a voltage-gated potassium channel subunit, consists of 1159 amino acids and features a complex architecture essential for its function. It comprises several distinct domains and regions that contribute to ion selectivity, channel gating, and regulatory interactions. At the N-terminus, two critical regions are present: the PAS domain (amino acids 41-70) and the PAC domain (amino acids 92-144). These domains are known to be involved in voltage sensing and the kinetics of channel inactivation. A disordered region is found from amino acids 231-314, contributing to the protein's flexibility.
Within the transmembrane region, the channel's selectivity filter, a highly conserved motif critical for differentiating potassium ions from other ions, is located between amino acids 624-629. Further towards the C-terminus, a cNMP-binding domain (cyclic nucleotide monophosphate-binding domain) is observed from amino acids 742-842, suggesting potential regulation by cyclic nucleotides. Additional disordered regions are present at amino acids 870-982 and 1015-1038, indicating areas of structural flexibility that may be important for protein-protein interactions or conformational changes during channel activity. Finally, a coiled-coil motif, extending from amino acids 1035-1062, is found towards the C-terminus, which may be involved in subunit assembly or interactions with other proteins.
Key variants
Variants within the KCNH2 gene can significantly impact the structure and function of the hERG potassium channel, leading to varied clinical consequences. These genetic alterations can range from single nucleotide substitutions to larger deletions or insertions. The effect of a specific variant often depends on its location within the gene and how it modifies the resulting protein. For instance, variants affecting critical domains involved in ion selectivity or voltage sensing can severely impair channel function, leading to conditions like Long QT Syndrome. The clinical interpretation of KCNH2 variants relies on a comprehensive assessment of genetic evidence, functional studies, and family history. Individuals carrying pathogenic or likely pathogenic variants in KCNH2 are at an increased risk for specific cardiac arrhythmias.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1498_1524del27 | p.Ile500_Phe508del | Pathogenic | ★★☆☆ | Long QT syndrome 2 |
c.1003C>T | p.Gln335Ter | Pathogenic | ★★☆☆ | Long QT syndrome |
c.100del | p.Ala34fs | Pathogenic | ★★☆☆ | Long QT syndrome |
c.1014del | p.Asn339fs | Pathogenic | ★★☆☆ | not provided |
c.1096C>T | p.Arg366Ter | Pathogenic | ★★☆☆ | not provided |
c.1102del | p.His368fs | Pathogenic/Likely pathogenic | ★★☆☆ | not provided |
c.1128G>A | p.Gln376= | Pathogenic/Likely pathogenic | ★★☆☆ | Long QT syndrome |
c.1129-1G>A | - | Pathogenic | ★★☆☆ | not provided |
c.1129-2A>G | - | Pathogenic | ★★☆☆ | not provided |
c.1139del | p.Leu380fs | Pathogenic/Likely pathogenic | ★★☆☆ | Long QT syndrome |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the KCNH2 gene are primarily associated with inherited cardiac rhythm disorders, particularly those affecting the repolarisation phase of the cardiac action potential. The most well-established condition linked to KCNH2 is Long QT syndrome type 2 [AD]. Mutations in this gene account for approximately 25 percent of cases of Romano-Ward syndrome, which is the most common form of long QT syndrome [PMID:17965005]. Conversely, certain KCNH2 variants have also been implicated in Short QT syndrome [AD], a rarer condition where cardiac repolarisation is abnormally abbreviated, increasing the risk of arrhythmias.
Inheritance pattern
Conditions caused by pathogenic KCNH2 variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
The KCNH2 gene is included in several NHS Genomic Medicine Service (GMS) pathways due to its clinical importance in inherited cardiac conditions. It is part of the 'Long QT syndrome' panel (R127) and the 'Short QT syndrome' panel (R130), both categorised as green. This indicates strong evidence for the gene's association with these conditions and that testing is routinely offered where clinically appropriate. This inclusion highlights its significance in the diagnosis and management of patients with suspected inherited arrhythmias within the UK health system.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Diet & lifestyle considerations
Adopting a heart-healthy lifestyle may be beneficial for individuals with KCNH2 variants, although it does not replace medical management. General recommendations, such as following a balanced diet rich in fruits, vegetables, and whole grains, and limiting intake of saturated fats, processed foods, and excessive sodium, contribute to overall cardiovascular health. Regular physical activity, appropriate for an individual's health status and undertaken with medical guidance, is also generally encouraged to support heart function. It is important for individuals to discuss any lifestyle modifications with their healthcare provider, particularly if they have a diagnosed cardiac condition. Managing stress through techniques like mindfulness or meditation and ensuring adequate sleep are also considered important components of a healthy lifestyle that may indirectly support cardiovascular wellbeing.
Supplement considerations
There is no conclusive evidence that specific dietary supplements can prevent, treat, or cure conditions associated with KCNH2 gene variants. While certain nutrients, such as magnesium and potassium, play roles in normal heart function, any supplementation should only be considered under the guidance of a healthcare professional. Individuals with KCNH2-related conditions should prioritise adhering to their prescribed medical treatments and lifestyle recommendations. Before taking any new supplement, it is crucial to consult with a doctor or a qualified healthcare provider to ensure it is safe and appropriate for their specific health needs, especially considering potential interactions with medications or underlying cardiac arrhythmias.
Frequently asked questions
What is the primary function of the KCNH2 gene?
The KCNH2 gene provides instructions for making an essential subunit of the hERG potassium channel, which is crucial for the electrical repolarisation of heart muscle cells, helping to maintain a regular heart rhythm.
What conditions are associated with variants in the KCNH2 gene?
Variants in the KCNH2 gene are primarily associated with inherited cardiac rhythm disorders, most notably Long QT Syndrome type 2 and, in some cases, Short QT Syndrome.
How do KCNH2 variants lead to heart rhythm problems?
KCNH2 variants can alter the function of the hERG potassium channel, affecting the electrical activity of heart cells. This can lead to either a prolonged or shortened repolarisation phase, resulting in abnormal heart rhythms.
Is KCNH2 testing available on the NHS?
Yes, the KCNH2 gene is included in NHS Genomic Medicine Service panels for conditions such as Long QT syndrome and Short QT syndrome, indicating its importance in clinical diagnosis within the UK.
Can lifestyle changes help manage KCNH2-related conditions?
While lifestyle changes such as a heart-healthy diet and regular exercise may support overall cardiovascular health, they do not replace medical management for KCNH2-related conditions. Any changes should be discussed with a healthcare provider.
Are there specific supplements recommended for KCNH2 gene variant carriers?
There is no conclusive evidence that specific dietary supplements can prevent or treat conditions associated with KCNH2 variants. Any discussion about supplements should involve a healthcare professional due to potential interactions and individual health needs.
References
- Smith JL, Anderson CL, Burgess DE. Molecular pathogenesis of long QT syndrome type 2. Journal of arrhythmia. 2016. PMID: 27761161
- McBride CM, Smith AM, Smith JL. Mechanistic basis for type 2 long QT syndrome caused by KCNH2 mutations that disrupt conserved arginine residues in the voltage sensor. The Journal of membrane biology. 2013. PMID: 23546015
- Sun Y, Quan XQ, Fromme S. A novel mutation in the KCNH2 gene associated with short QT syndrome. Journal of molecular and cellular cardiology. 2011. PMID: 21130771
- Sanguinetti MC. HERG1 channelopathies. Pflugers Archiv : European journal of physiology. 2010. PMID: 20544339
- Hong K, Bjerregaard P, Gussak I. Short QT syndrome and atrial fibrillation caused by mutation in KCNH2. Journal of cardiovascular electrophysiology. 2005. PMID: 15828882
- Schimpf R, Wolpert C, Gaita F. Short QT syndrome. Cardiovascular research. 2005. PMID: 15890322
- Paulussen AD, Raes A, Jongbloed RJ. HERG mutation predicts short QT based on channel kinetics but causes long QT by heterotetrameric trafficking deficiency. Cardiovascular research. 2005. PMID: 15958262
- Cordeiro JM, Brugada R, Wu YS. Modulation of I(Kr) inactivation by mutation N588K in KCNH2: a link to arrhythmogenesis in short QT syndrome. Cardiovascular research. 2005. PMID: 16039272
- Brugada R, Hong K, Dumaine R. Sudden death associated with short-QT syndrome linked to mutations in HERG. Circulation. 2004. PMID: 14676148
- Paulussen AD, Gilissen RA, Armstrong M. Genetic variations of KCNQ1, KCNH2, SCN5A, KCNE1, and KCNE2 in drug-induced long QT syndrome patients. Journal of molecular medicine (Berlin, Germany). 2004. PMID: 14760488
- Thomas D, Kiehn J, Katus HA. Defective protein trafficking in hERG-associated hereditary long QT syndrome (LQT2): molecular mechanisms and restoration of intracellular protein processing. Cardiovascular research. 2003. PMID: 14613852
- Adam MP, Bick S, Mirzaa GM. Long QT Syndrome Overview. 1993. PMID: 20301308