KCNE2

Last updated
KCNE2
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases KCNE2 , ATFB4, LQT5, LQT6, MIRP1, potassium voltage-gated channel subfamily E regulatory subunit 2
External IDs OMIM: 603796 MGI: 1891123 HomoloGene: 71688 GeneCards: KCNE2
Orthologs
SpeciesHumanMouse
Entrez

9992

246133

Ensembl

ENSG00000159197

ENSMUSG00000039672

UniProt

Q9Y6J6

Q9D808

RefSeq (mRNA)

NM_172201
NM_005136

NM_134110
NM_001358372

RefSeq (protein)

NP_751951

NP_598871
NP_001345301

Location (UCSC) Chr 21: 34.36 – 34.37 Mb Chr 16: 92.09 – 92.1 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse
KCNE2 3D animation

Potassium voltage-gated channel subfamily E member 2 (KCNE2), also known as MinK-related peptide 1 (MiRP1), is a protein that in humans is encoded by the KCNE2 gene on chromosome 21. [5] [6] MiRP1 is a voltage-gated potassium channel accessory subunit (beta subunit) associated with Long QT syndrome. [5] It is ubiquitously expressed in many tissues and cell types. [7] Because of this and its ability to regulate multiple different ion channels, KCNE2 exerts considerable influence on a number of cell types and tissues. [5] [8] Human KCNE2 is a member of the five-strong family of human KCNE genes. KCNE proteins contain a single membrane-spanning region, extracellular N-terminal and intracellular C-terminal. KCNE proteins have been widely studied for their roles in the heart and in genetic predisposition to inherited cardiac arrhythmias. The KCNE2 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease. [9] More recently, roles for KCNE proteins in a variety of non-cardiac tissues have also been explored.

Contents

Discovery

Steve Goldstein (then at Yale University) used a BLAST search strategy, focusing on KCNE1 sequence stretches known to be important for function, to identify related expressed sequence tags (ESTs) in the NCBI database. Using sequences from these ESTs, KCNE2, 3 and 4 were cloned. [5]

Tissue distribution

KCNE2 protein is most readily detected in the choroid plexus epithelium, gastric parietal cells, and thyroid epithelial cells. KCNE2 is also expressed in atrial and ventricular cardiomyocytes, the pancreas, pituitary gland, and lung epithelium. In situ hybridization data suggest that KCNE2 transcript may also be expressed in various neuronal populations. [10]

Structure

Gene

The KCNE2 gene resides on chromosome 21 at the band 21q22.11 and contains 2 exons. [6] Since human KCNE2 is located ~79 kb from KCNE1 and in the opposite direction, KCNE2 is proposed to originate from a gene duplication event. [11]

Protein

This protein belongs to the potassium channel KCNE family and is one five single transmembrane domain voltage-gated potassium (Kv) channel ancillary subunits. [12] [13] KCNE2 is composed of three major domains: the N-terminal domain, the transmembrane domain, and the C-terminal domain. The N-terminal domain protrudes out of the extracellular side of the cell membrane and is, thus, soluble in the aqueous environment. Meanwhile, the transmembrane and C-terminal domains are lipid-soluble to enable the protein to incorporate into the cell membrane. [13] The C-terminal faces the intracellular side of the membrane and may share a putative PKC phosphorylation site with other KCNE proteins.

Like other KCNEs, KCNE2 forms a heteromeric complex with the Kv α subunits. [11]

Function

Choroid plexus epithelium

KCNE2 protein is most readily detected in the choroid plexus epithelium, at the apical side. KCNE2 forms complexes there with the voltage-gated potassium channel α subunit, Kv1.3. In addition, KCNE2 forms reciprocally regulating tripartite complexes in the choroid plexus epithelium with the KCNQ1 α subunit and the sodium-dependent myo-inositol transporter, SMIT1. Kcne2-/- mice exhibit increased seizure susceptibility, reduced immobility time in the tail suspension test, and reduced cerebrospinal fluid myo-inositol content, compared to wild-type littermates. Mega-dosing of myo-inositol reverses all these phenotypes, suggesting a link between myo-inositol and the seizure susceptibility and behavioral alterations in Kcne2-/- mice. [14] [15]

Gastric epithelium

KCNE2 is also highly expressed in parietal cells of the gastric epithelium, also at the apical side. In these cells, KCNQ1-KCNE2 K+ channels, which are constitutively active, provide a conduit to return K+ ions back to the stomach lumen. The K+ ions enter the parietal cell through the gastric H+/K+-ATPase, which swaps them for protons as it acidifies the stomach. While KCNQ1 channels are inhibited by low extracellular pH, KCNQ1-KCNE2 channels activity is augmented by extracellular protons, an ideal characteristic for their role in parietal cells. [16] [17] [18]

Thyroid epithelium

KCNE2 forms constitutively active K+ channels with KCNQ1 in the basolateral membrane of thyroid epithelial cells. Kcne2-/- mice exhibit hypothyroidism, particularly apparent during gestation or lactation. KCNQ1-KCNE2 is required for optimal iodide uptake into the thyroid by the basolateral sodium iodide symporter (NIS). Iodide is required for biosynthesis of thyroid hormones. [19] [20]

Heart

KCNE2 was originally discovered to regulate hERG channel function. KCNE2 decreases macroscopic and unitary current through hERG, and speeds hERG deactivation. hERG generates IKr, the most prominent repolarizing current in human ventricular cardiomyocytes. hERG, and IKr, are highly susceptible to block by a range of structurally diverse pharmacological agents. This property means that many drugs or potential drugs have the capacity to impair human ventricular repolarization, leading to drug-induced long QT syndrome. [5] KCNE2 may also regulate hyperpolarization-activated, cyclic-nucleotide-gated (HCN) pacemaker channels in human heart and in the hearts of other species, as well as the Cav1.2 voltage-gated calcium channel. [21] [22]

In mice, mERG and KCNQ1, another Kv α subunit regulated by KCNE2, are neither influential nor highly expressed in adult ventricles. However, Kcne2-/- mice exhibit QT prolongation at baseline at 7 months of age, or earlier if provoked with a QT-prolonging agent such as sevoflurane. This is because KCNE2 is a promiscuous regulatory subunit that forms complexes with Kv1.5 and with Kv4.2 in adult mouse ventricular myocytes. KCNE2 increases currents though Kv4.2 channels and slows their inactivation. KCNE2 is required for Kv1.5 to localize to the intercalated discs of mouse ventricular myocytes. Kcne2 deletion in mice reduces the native currents generated in ventricular myocytes by Kv4.2 and Kv1.5, namely Ito and IKslow, respectively. [23]

Clinical Significance

Gastric epithelium

Kcne2-/- mice exhibit achlorhydria, gastric hyperplasia, and mis-trafficking of KCNQ1 to the parietal cell basal membrane. The mis-trafficking occurs because KCNE3 is upregulated in the parietal cells of Kcne2-/- mice, and hijacks KCNQ1, taking it to the basolateral membrane. When both Kcne2 and Kcne3 are germline-deleted in mice, KCNQ1 traffics to the parietal cell apical membrane but the gastric phenotype is even worse than for Kcne2-/- mice, emphasizing that KCNQ1 requires KCNE2 co-assembly for functional attributes other than targeting in parietal cells. Kcne2-/- mice also develop gastritis cystica profunda and gastric neoplasia. Human KCNE2 downregulation is also observed in sites of gastritis cystica profunda and gastric adenocarcinoma. [16] [17] [18]

Thyroid epithelium

Positron emission tomography data show that with KCNE2, 124I uptake by the thyroid is impaired. Kcne2 deletion does not impair organification of iodide once it has been taken up by NIS. Pups raised by Kcne2-/- dams are particularly severely affected becauset they receive less milk (hypothyroidism of the dams impairs milk ejection), the milk they receive is deficient in T4, and they themselves cannot adequately transport iodide into the thyroid. Kcne2-/- pups exhibit stunted growth, alopecia, cardiomegaly and reduced cardiac ejection fraction, all of which are alleviated by thyroid hormone supplementation of pups or dams. Surrogating Kcne2-/- pups with Kcne2+/+ dams also alleviates these phenotypes, highlighting the influence of maternal genotype in this case. [19] [20]

Heart

As observed for hERG mutations, KCNE2 loss-of-function mutations are associated with inherited long QT syndrome, and hERG-KCNE2 channels carrying the mutations show reduced activity compared to wild-type channels. In addition, some KCNE2 mutations and also more common polymorphisms are associated with drug-induced long QT syndrome. In several cases, specific KCNE2 sequence variants increase the susceptibility to hERG-KCNE2 channel inhibition by the drug that precipitated the QT prolongation in the patient from which the gene variant was isolated. [5] [24] Long QT syndrome predisposes to potentially lethal ventricular cardiac arrhythmias including torsades de pointe, which can degenerate into ventricular fibrillation and sudden cardiac death. [5] Moreover, KCNE2 gene variation can disrupt HCN1-KCNE2 channel function and this may potentially contribute to cardiac arrhythmogenesis. [21] KCNE2 is also associated with familial atrial fibrillation, which may involve excessive KCNQ1-KCNE2 current caused by KCNE2 gain-of-function mutations. [25] [26]

Recently, a battery of extracardiac effects were discovered in Kcne2-/- mice that may contribute to cardiac arrhythmogenesis in Kcne2-/- mice and could potentially contribute to human cardiac arrhythmias if similar effects are observed in human populations. Kcne2 deletion in mice causes anemia, glucose intolerance, dyslipidemia, hyperkalemia and elevated serum angiotensin II. Some or all of these might contribute to predisposition to sudden cardiac death in Kcne2-/- mice in the context of myocardial ischemia and post-ischemic arrhythmogenesis. [27]

Clinical Marker

A multi-locus genetic risk score study based on a combination of 27 loci, including the KCNE2 gene, identified individuals at increased risk for both incident and recurrent coronary artery disease events, as well as an enhanced clinical benefit from statin therapy. The study was based on a community cohort study (the Malmo Diet and Cancer study) and four additional randomized controlled trials of primary prevention cohorts (JUPITER and ASCOT) and secondary prevention cohorts (CARE and PROVE IT-TIMI 22). [9]

See also

Notes

Related Research Articles

<span class="mw-page-title-main">Long QT syndrome</span> Medical condition

Long QT syndrome (LQTS) is a condition affecting repolarization (relaxing) of the heart after a heartbeat, giving rise to an abnormally lengthy QT interval. It results in an increased risk of an irregular heartbeat which can result in fainting, drowning, seizures, or sudden death. These episodes can be triggered by exercise or stress. Some rare forms of LQTS are associated with other symptoms and signs including deafness and periods of muscle weakness.

<span class="mw-page-title-main">Jervell and Lange-Nielsen syndrome</span> Medical condition

Jervell and Lange-Nielsen syndrome (JLNS) is a rare type of long QT syndrome associated with severe, bilateral sensorineural hearing loss. Those with JLNS are at risk of abnormal heart rhythms called arrhythmias, which can lead to fainting, seizures, or sudden death. JLNS, like other forms of long QT syndrome, causes the cardiac muscle to take longer than usual to recharge between beats. It is caused by genetic variants responsible for producing ion channels that carry transport potassium out of cells. The condition is usually diagnosed using an electrocardiogram, but genetic testing can also be used. Treatment includes lifestyle measures, beta blockers, and implantation of a defibrillator in some cases. It was first described by Anton Jervell and Fred Lange-Nielsen in 1957.

<span class="mw-page-title-main">Romano–Ward syndrome</span> Medical condition

Romano–Ward syndrome is the most common form of congenital Long QT syndrome (LQTS), a genetic heart condition that affects the electrical properties of heart muscle cells. Those affected are at risk of abnormal heart rhythms which can lead to fainting, seizures, or sudden death. Romano–Ward syndrome can be distinguished clinically from other forms of inherited LQTS as it affects only the electrical properties of the heart, while other forms of LQTS can also affect other parts of the body.

<span class="mw-page-title-main">Andersen–Tawil syndrome</span> Rare autosomal dominant genetic disorder

Andersen–Tawil syndrome, also called Andersen syndrome and long QT syndrome 7, is a rare genetic disorder affecting several parts of the body. The three predominant features of Andersen–Tawil syndrome include disturbances of the electrical function of the heart characterised by an abnormality seen on an electrocardiogram and a tendency to abnormal heart rhythms, physical characteristics including low-set ears and a small lower jaw, and intermittent periods of muscle weakness known as hypokalaemic periodic paralysis.

<span class="mw-page-title-main">KvLQT1</span>

Kv7.1 (KvLQT1) is a potassium channel protein whose primary subunit in humans is encoded by the KCNQ1 gene. Kv7.1 is a voltage and lipid-gated potassium channel present in the cell membranes of cardiac tissue and in inner ear neurons among other tissues. In the cardiac cells, Kv7.1 mediates the IKs (or slow delayed rectifying K+) current that contributes to the repolarization of the cell, terminating the cardiac action potential and thereby the heart's contraction. It is a member of the KCNQ family of potassium channels.

hERG Mammalian protein found in humans

hERG is a gene that codes for a protein known as Kv11.1, the alpha subunit of a potassium ion channel. This ion channel is best known for its contribution to the electrical activity of the heart: the hERG channel mediates the repolarizing IKr current in the cardiac action potential, which helps coordinate the heart's beating.

<span class="mw-page-title-main">Voltage-gated potassium channel</span> Class of transport proteins

Voltage-gated potassium channels (VGKCs) are transmembrane channels specific for potassium and sensitive to voltage changes in the cell's membrane potential. During action potentials, they play a crucial role in returning the depolarized cell to a resting state.

<span class="mw-page-title-main">KCNE1</span> Protein-coding gene in the species Homo sapiens

Potassium voltage-gated channel subfamily E member 1 is a protein that in humans is encoded by the KCNE1 gene.

<span class="mw-page-title-main">KvLQT2</span>

Kv7.2 (KvLQT2) is a voltage- and lipid-gated potassium channel protein coded for by the gene KCNQ2.

<span class="mw-page-title-main">KvLQT3</span> Protein-coding gene in the species Homo sapiens

Kv7.3 (KvLQT3) is a potassium channel protein coded for by the gene KCNQ3.

<span class="mw-page-title-main">KCNA5</span> Protein-coding gene in the species Homo sapiens

Potassium voltage-gated channel, shaker-related subfamily, member 5, also known as KCNA5 or Kv1.5, is a protein that in humans is encoded by the KCNA5 gene.

<span class="mw-page-title-main">KCNE3</span>

Potassium voltage-gated channel, Isk-related family, member 3 (KCNE3), also known as MinK-related peptide 2(MiRP2) is a protein that in humans is encoded by the KCNE3 gene.

<span class="mw-page-title-main">KCND3</span>

Potassium voltage-gated channel subfamily D member 3 also known as Kv4.3 is a protein that in humans is encoded by the KCND3 gene. It contributes to the cardiac transient outward potassium current (Ito1), the main contributing current to the repolarizing phase 1 of the cardiac action potential.

<span class="mw-page-title-main">KCNH1</span>

Potassium voltage-gated channel subfamily H member 1 is a protein that in humans is encoded by the KCNH1 gene.

<span class="mw-page-title-main">KCNE4</span>

Potassium voltage-gated channel subfamily E member 4, originally named MinK-related peptide 3 or MiRP3 when it was discovered, is a protein that in humans is encoded by the KCNE4 gene.

<span class="mw-page-title-main">KCNE5</span> Protein-coding gene in the species Homo sapiens

KCNE1-like also known as KCNE1L is a protein that in humans is encoded by the KCNE1L gene.

BmTx3 is a neurotoxin, which is a component of the venom of the scorpion Buthus Martensi Karsch. It blocks A-type potassium channels in the central nervous system and hERG-channels in the heart.

<span class="mw-page-title-main">E-4031</span> Chemical compound

E-4031 is an experimental class III antiarrhythmic drug that blocks potassium channels of the hERG-type.

<span class="mw-page-title-main">Cardiac transient outward potassium current</span> Ion current

The cardiac transient outward potassium current (referred to as Ito1 or Ito ) is one of the ion currents across the cell membrane of heart muscle cells. It is the main contributing current during the repolarizing phase 1 of the cardiac action potential. It is a result of the movement of positively charged potassium (K+) ions from the intracellular to the extracellular space. Ito1 is complemented with Ito2 resulting from Cl− ions to form the transient outward current Ito.

<span class="mw-page-title-main">SGK1</span>

Serine/threonine-protein kinase Sgk1 also known as serum and glucocorticoid-regulated kinase 1 is an enzyme that in humans is encoded by the SGK1 gene.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000159197 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000039672 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. 1 2 3 4 5 6 7 Abbott GW, Sesti F, Splawski I, Buck ME, Lehmann MH, Timothy KW, Keating MT, Goldstein SA (April 1999). "MiRP1 forms IKr potassium channels with HERG and is associated with cardiac arrhythmia". Cell. 97 (2): 175–87. doi: 10.1016/S0092-8674(00)80728-X . PMID   10219239. S2CID   8507168.
  6. 1 2 "KCNE2 potassium voltage-gated channel subfamily E regulatory subunit 2 [Homo sapiens (human)] - Gene - NCBI". www.ncbi.nlm.nih.gov. Retrieved 2016-10-10.
  7. ↑ "BioGPS - your Gene Portal System". biogps.org. Retrieved 2016-10-10.
  8. ↑ Abbott GW (2012). "KCNE2 and the K (+) channel: the tail wagging the dog". Channels. 6 (1): 1–10. doi:10.4161/chan.19126. PMC   3367673 . PMID   22513486.
  9. 1 2 Mega JL, Stitziel NO, Smith JG, Chasman DI, Caulfield MJ, Devlin JJ, Nordio F, Hyde CL, Cannon CP, Sacks FM, Poulter NR, Sever PS, Ridker PM, Braunwald E, Melander O, Kathiresan S, Sabatine MS (June 2015). "Genetic risk, coronary heart disease events, and the clinical benefit of statin therapy: an analysis of primary and secondary prevention trials". Lancet. 385 (9984): 2264–71. doi:10.1016/S0140-6736(14)61730-X. PMC   4608367 . PMID   25748612.
  10. ↑ Tinel N, Diochot S, Lauritzen I, Barhanin J, Lazdunski M, Borsotto M (September 2000). "M-type KCNQ2-KCNQ3 potassium channels are modulated by the KCNE2 subunit". FEBS Letters. 480 (2–3): 137–41. doi: 10.1016/s0014-5793(00)01918-9 . PMID   11034315. S2CID   8386123.
  11. 1 2 Abbott GW (September 2015). "The KCNE2 K+ channel regulatory subunit: Ubiquitous influence, complex pathobiology". Gene. 569 (2): 162–72. doi:10.1016/j.gene.2015.06.061. PMC   4917011 . PMID   26123744.
  12. ↑ "KCNE2 - Potassium voltage-gated channel subfamily E member 2 - Homo sapiens (Human) - KCNE2 gene & protein". www.uniprot.org. Retrieved 2016-10-10.
  13. 1 2 Abbott GW, Ramesh B, Srai SK (2008-01-01). "Secondary structure of the MiRP1 (KCNE2) potassium channel ancillary subunit". Protein and Peptide Letters. 15 (1): 63–75. doi:10.2174/092986608783330413. PMID   18221016.
  14. ↑ Abbott GW, Tai KK, Neverisky DL, Hansler A, Hu Z, Roepke TK, Lerner DJ, Chen Q, Liu L, Zupan B, Toth M, Haynes R, Huang X, Demirbas D, Buccafusca R, Gross SS, Kanda VA, Berry GT (March 2014). "KCNQ1, KCNE2, and Na+-coupled solute transporters form reciprocally regulating complexes that affect neuronal excitability". Science Signaling. 7 (315): ra22. doi:10.1126/scisignal.2005025. PMC   4063528 . PMID   24595108.
  15. ↑ Roepke TK, Kanda VA, Purtell K, King EC, Lerner DJ, Abbott GW (December 2011). "KCNE2 forms potassium channels with KCNA3 and KCNQ1 in the choroid plexus epithelium". FASEB Journal. 25 (12): 4264–73. doi:10.1096/fj.11-187609. PMC   3236621 . PMID   21859894.
  16. 1 2 Roepke TK, Anantharam A, Kirchhoff P, Busque SM, Young JB, Geibel JP, Lerner DJ, Abbott GW (August 2006). "The KCNE2 potassium channel ancillary subunit is essential for gastric acid secretion". The Journal of Biological Chemistry. 281 (33): 23740–7. doi: 10.1074/jbc.M604155200 . PMID   16754665.
  17. 1 2 Roepke TK, Purtell K, King EC, La Perle KM, Lerner DJ, Abbott GW (6 July 2010). "Targeted deletion of Kcne2 causes gastritis cystica profunda and gastric neoplasia". PLOS ONE. 5 (7): e11451. Bibcode:2010PLoSO...511451R. doi: 10.1371/journal.pone.0011451 . PMC   2897890 . PMID   20625512.
  18. 1 2 Roepke TK, King EC, Purtell K, Kanda VA, Lerner DJ, Abbott GW (February 2011). "Genetic dissection reveals unexpected influence of beta subunits on KCNQ1 K+ channel polarized trafficking in vivo". FASEB Journal. 25 (2): 727–36. doi:10.1096/fj.10-173682. PMC   3023397 . PMID   21084694.
  19. 1 2 Roepke TK, King EC, Reyna-Neyra A, Paroder M, Purtell K, Koba W, Fine E, Lerner DJ, Carrasco N, Abbott GW (October 2009). "Kcne2 deletion uncovers its crucial role in thyroid hormone biosynthesis". Nature Medicine. 15 (10): 1186–94. doi:10.1038/nm.2029. PMC   2790327 . PMID   19767733.
  20. 1 2 Purtell K, Paroder-Belenitsky M, Reyna-Neyra A, Nicola JP, Koba W, Fine E, Carrasco N, Abbott GW (August 2012). "The KCNQ1-KCNE2 K+ channel is required for adequate thyroid I− uptake". FASEB Journal. 26 (8): 3252–9. doi:10.1096/fj.12-206110. PMC   3405278 . PMID   22549510.
  21. 1 2 Nawathe PA, Kryukova Y, Oren RV, Milanesi R, Clancy CE, Lu JT, Moss AJ, Difrancesco D, Robinson RB (September 2013). "An LQTS6 MiRP1 mutation suppresses pacemaker current and is associated with sinus bradycardia". Journal of Cardiovascular Electrophysiology. 24 (9): 1021–7. doi:10.1111/jce.12163. PMC   4059362 . PMID   23631727.
  22. ↑ Liu W, Deng J, Wang G, Zhang C, Luo X, Yan D, Su Q, Liu J (July 2014). "KCNE2 modulates cardiac L-type Ca(2+) channel". Journal of Molecular and Cellular Cardiology. 72: 208–18. doi:10.1016/j.yjmcc.2014.03.013. PMID   24681347. S2CID   7271200.
  23. ↑ Roepke TK, Kontogeorgis A, Ovanez C, Xu X, Young JB, Purtell K, Goldstein PA, Christini DJ, Peters NS, Akar FG, Gutstein DE, Lerner DJ, Abbott GW (October 2008). "Targeted deletion of kcne2 impairs ventricular repolarization via disruption of I(K,slow1) and I(to,f)". FASEB Journal. 22 (10): 3648–60. doi:10.1096/fj.08-110171. PMC   2537427 . PMID   18603586.
  24. ↑ Sesti F, Abbott GW, Wei J, Murray KT, Saksena S, Schwartz PJ, Priori SG, Roden DM, George AL, Goldstein SA (September 2000). "A common polymorphism associated with antibiotic-induced cardiac arrhythmia". Proceedings of the National Academy of Sciences of the United States of America. 97 (19): 10613–8. Bibcode:2000PNAS...9710613S. doi: 10.1073/pnas.180223197 . PMC   27073 . PMID   10984545.
  25. ↑ Yang Y, Xia M, Jin Q, Bendahhou S, Shi J, Chen Y, Liang B, Lin J, Liu Y, Liu B, Zhou Q, Zhang D, Wang R, Ma N, Su X, Niu K, Pei Y, Xu W, Chen Z, Wan H, Cui J, Barhanin J, Chen Y (November 2004). "Identification of a KCNE2 gain-of-function mutation in patients with familial atrial fibrillation". American Journal of Human Genetics. 75 (5): 899–905. doi:10.1086/425342. PMC   1182120 . PMID   15368194.
  26. ↑ Nielsen JB, Bentzen BH, Olesen MS, David JP, Olesen SP, Haunsø S, Svendsen JH, Schmitt N (2014). "Gain-of-function mutations in potassium channel subunit KCNE2 associated with early-onset lone atrial fibrillation". Biomarkers in Medicine . 8 (4): 557–70. doi:10.2217/bmm.13.137. PMID   24796621.
  27. ↑ Hu Z, Kant R, Anand M, King EC, Krogh-Madsen T, Christini DJ, Abbott GW (February 2014). "Kcne2 deletion creates a multisystem syndrome predisposing to sudden cardiac death". Circulation: Cardiovascular Genetics. 7 (1): 33–42. doi:10.1161/CIRCGENETICS.113.000315. PMC   4917016 . PMID   24403551.

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