KCNH1

{{Short description|Protein-coding gene in the species Homo sapiens}}

Potassium voltage-gated channel subfamily H member 1 (K_V10.1, EAG1) is a protein that in humans is encoded by the KCNH1 gene.{{cite journal | vauthors = Occhiodoro T, Bernheim L, Liu JH, Bijlenga P, Sinnreich M, Bader CR, Fischer-Lougheed J | title = Cloning of a human ether-a-go-go potassium channel expressed in myoblasts at the onset of fusion | journal = FEBS Letters | volume = 434 | issue = 1–2 | pages = 177–182 | date = August 1998 | pmid = 9738473 | doi = 10.1016/S0014-5793(98)00973-9 | doi-access = free | bibcode = 1998FEBSL.434..177O }}{{cite journal | vauthors = Gutman GA, Chandy KG, Grissmer S, Lazdunski M, McKinnon D, Pardo LA, Robertson GA, Rudy B, Sanguinetti MC, Stühmer W, Wang X | title = International Union of Pharmacology. LIII. Nomenclature and molecular relationships of voltage-gated potassium channels | journal = Pharmacological Reviews | volume = 57 | issue = 4 | pages = 473–508 | date = December 2005 | pmid = 16382104 | doi = 10.1124/pr.57.4.10 | s2cid = 219195192 }}{{cite web | title = Entrez Gene: KCNH1 potassium voltage-gated channel, subfamily H (eag-related), member 1 | url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=3756 }} Mutations in KCNH1 cause genetic epilepsy and developmental encephalopathies, and aberant expression is associated with tumor progression.

Function

Expression of KCNH1 is predominantly restricted to the adult central nervous system.{{cite web | title = 603305 - Potassium channel, voltage-gated; subfamily H, member 1; KCNH1 | url = https://www.omim.org/entry/603305 | work = Online Mendelian Inheritance in Man (OMIM) }} The KCNH1 gene encodes a homotetrameric highly-conserved voltage-gated potassium channel (K_V10.1) thought to be responsible for reestablishing the membrane potential of excitatory neurons in response to high frequency firing.{{Cite journal | vauthors = Schmidt H, Farsi Z, Barrantes-Freer A, Rubio ME, Ufartes R, Eilers J, Sakaba T, Stühmer W, Pardo LA, Mortensen LS | title = KV10.1 opposes activity-dependent increase in Ca2+ influx into the presynaptic terminal of the parallel fibre–Purkinje cell synapse | journal = The Journal of Physiology | volume = 593 | issue = 1 | pages = 181–196 | date = 2015 | pmid = 25556795 | pmc = 4293062 | doi = 10.1113/jphysiol.2014.281600 | language = en | issn = 1469-7793 }}

K_V10.1 is a non-inactivating delayed rectifier potassium channel. Like other voltage-gated potassium ion channels, opening of the K_V10.1 channel pore is triggered by membrane depolarisation, which results in an outward flow of potassium ions to rectify the baseline membrane potential. K_V10.1 is slow to open when triggered and does not undergo an inactivation state after closing.

Structurally, K_V10.1 is composed of four identical subunits that are each 989 residues long (111.4 kDa). Each subunit is composed of a PAS domain, transmembrane voltage-sensing and pore domains, a C-linker, and an intracellular cyclic nucleotide-binding homology domain. Alternative splicing of this gene results in two transcript variants encoding distinct isoforms that differ by the inclusion or exclusion of 27 amino acids between the S3 and S4 helices of the voltage-sensing domain.

KCNH1 expression is activated at the onset of myoblast differentiation and known to play roles in the cell cycle and cell proliferation.{{Cite journal | vauthors = del Camino D, Sánchez A, Alves F, Brüggemann A, Beckh S, Stühmer W, Pardo LA | title = Oncogenic potential of EAG K+ channels | journal = The EMBO Journal | volume = 18 | issue = 20 | pages = 5540–5547 | date = 1999-10-15 | pmid = 10523298 | pmc = 1171622 | doi = 10.1093/emboj/18.20.5540 | url = https://www.embopress.org/doi/full/10.1093/emboj/18.20.5540 | issn = 0261-4189 }}

Pathologies

Gabbett and colleagues described Temple–Baraitser syndrome (TBS) in 2008, naming the condition after English clinical geneticists Profs Karen Temple and Michael Baraitser.{{cite journal | vauthors = Gabbett MT, Clark RC, McGaughran JM | title = A second case of severe mental retardation and absent nails of hallux and pollex (Temple-Baraitser syndrome) | journal = American Journal of Medical Genetics. Part A | volume = 146A | issue = 4 | pages = 450–452 | date = February 2008 | pmid = 18203178 | doi = 10.1002/ajmg.a.32129 | s2cid = 2532859 }} TBS is categorized by intellectual disabilities, epilepsy, atypical facial features, and aplasia of the nails.

It was later demonstrated that de novo missense mutations in the KCNH1 gene cause deleterious gain of function in the voltage-gated potassium channel, resulting in TBS.{{cite journal | vauthors = Simons C, Rash LD, Crawford J, Ma L, Cristofori-Armstrong B, Miller D, Ru K, Baillie GJ, Alanay Y, Jacquinet A, Debray FG, Verloes A, Shen J, Yesil G, Guler S, Yuksel A, Cleary JG, Grimmond SM, McGaughran J, King GF, Gabbett MT, Taft RJ | title = Mutations in the voltage-gated potassium channel gene KCNH1 cause Temple-Baraitser syndrome and epilepsy | journal = Nature Genetics | volume = 47 | issue = 1 | pages = 73–77 | date = January 2015 | pmid = 25420144 | doi = 10.1038/ng.3153 | s2cid = 52799681 }} Patients with de novo mutations in KCNH1 were found to be affected by epilepsy, while children born with germline mutations from mosaic probands were affected by TBS. This provides further evidence of the role that genetic mosaicism plays in the etiology of neurological disorders. Type 1 Zimmermann–Laband syndrome was later found to be caused by similar missense mutations in KCNH1.{{cite journal | vauthors = Kortüm F, Caputo V, Bauer CK, Stella L, Ciolfi A, Alawi M, Bocchinfuso G, Flex E, Paolacci S, Dentici ML, Grammatico P, Korenke GC, Leuzzi V, Mowat D, Nair LD, Nguyen TT, Thierry P, White SM, Dallapiccola B, Pizzuti A, Campeau PM, Tartaglia M, Kutsche K | title = Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome | journal = Nature Genetics | volume = 47 | issue = 6 | pages = 661–667 | date = June 2015 | pmid = 25915598 | doi = 10.1038/ng.3282 | hdl = 2108/118197 | s2cid = 12060592 | hdl-access = free }} This has led some researchers to believe that type 1 Zimmermann-Laband and Temple-Baraitser syndromes are different manifestations of the same disorder.{{cite journal | vauthors = Mégarbané A, Al-Ali R, Choucair N, Lek M, Wang E, Ladjimi M, Rose CM, Hobeika R, Macary Y, Temanni R, Jithesh PV, Chouchane A, Sastry KS, Thomas R, Tomei S, Liu W, Marincola FM, MacArthur D, Chouchane L | title = Temple-Baraitser Syndrome and Zimmermann-Laband Syndrome: one clinical entity? | journal = BMC Medical Genetics | volume = 17 | issue = 1 | pages = 42 | date = June 2016 | pmid = 27282200 | pmc = 4901505 | doi = 10.1186/s12881-016-0304-4 | doi-access = free }}{{cite journal | vauthors = Bramswig NC, Ockeloen CW, Czeschik JC, van Essen AJ, Pfundt R, Smeitink J, Poll-The BT, Engels H, Strom TM, Wieczorek D, Kleefstra T, Lüdecke HJ | title = 'Splitting versus lumping': Temple-Baraitser and Zimmermann-Laband Syndromes | journal = Human Genetics | volume = 134 | issue = 10 | pages = 1089–1097 | date = October 2015 | pmid = 26264464 | doi = 10.1007/s00439-015-1590-1 | s2cid = 14238362 }}

Overexpression of KCNH1 may confer a growth advantage to cancer cells and favor tumor cell proliferation, as KCNH1 overexpression has been observed in 70% of solid tumors.{{Cite journal | vauthors = Tomczak AP, Zahed F, Stühmer W, Pardo LA, Urrego D | title = Potassium channels in cell cycle and cell proliferation | journal = Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences | volume = 369 | issue = 1638 | pages = 20130094 | date = 2014-03-19 | pmid = 24493742 | pmc = 3917348 | doi = 10.1098/rstb.2013.0094 }}

Interactions

KCNH1 has been shown to interact with KCNB1{{cite journal | vauthors = Ottschytsch N, Raes A, Van Hoorick D, Snyders DJ | title = Obligatory heterotetramerization of three previously uncharacterized Kv channel alpha-subunits identified in the human genome | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 99 | issue = 12 | pages = 7986–7991 | date = June 2002 | pmid = 12060745 | pmc = 123007 | doi = 10.1073/pnas.122617999 | bibcode = 2002PNAS...99.7986O | doi-access = free }} and is inhibited by the highly-conserved secondary messenger calmodulin in the presence of calcium.

References

External links

{{MeshName|KCNH1+protein,+human}}
{{MeshName|Kv10.1+Potassium+Channel}}
[https://humandiseasegenes.nl/kcnh1 Human Disease Genes - KCNH1]

{{Medical resources

| OMIM = 603305

}}

Category:PAS-domain-containing proteins