Potassium voltage-gated channel subfamily H member 1 (KV10.1, EAG1) is anion channelprotein that in humans is encoded by theKCNH1gene.[5][6][7] Disease-causing (pathogenic) mutations in theKCNH1 gene causeKCNH1-related disorders, which can include symptoms such as mild-to-severe developmental delay, profound intellectual disability, neonatal hypotonia, myopathic facial appearance, and infantile-onset seizures. Aberrant overexpression ofKCNH1 is associated with tumor progression.
Expression of KCNH1 is predominantly restricted to the adult central nervous system.[8] TheKCNH1gene encodes ahomotetrameric highly-conservedvoltage-gated potassium channel (KV10.1) thought to be responsible for reestablishing the membrane potential of excitatory neurons in response to high frequency firing.[9]
KV10.1 is a non-inactivating delayed rectifier potassium channel. Like other voltage-gated potassium ion channels, opening of the KV10.1 channel pore is triggered by membrane depolarisation, which results in an outward flow of potassium ions to rectify the baseline membrane potential. KV10.1 is slow to open when triggered and does not undergo an inactivation state after closing.
Structurally, KV10.1 is composed of four identical subunits that are each 989 residues long (111.4 kDa). Each subunit is composed of aPAS domain,transmembrane voltage-sensing and pore domains, a C-linker, and an intracellularcyclic 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.[7]
KCNH1 expression is activated incilia at the onset of myoblast differentiation and known to play roles in the cell cycle and cell proliferation.[10]
Gabbett and colleagues describedTemple–Baraitser syndrome (TBS) in 2008, naming the condition after Englishclinical geneticists Profs Karen Temple and Michael Baraitser.[11] TBS is categorized by intellectual disabilities, epilepsy, atypical facial features, and aplasia of the nails. It was later demonstrated thatde novo missense mutations in theKCNH1 gene cause deleterious gain of function in thevoltage-gated potassium channel KV10.1, resulting in TBS.[12] Patients withde novo mutations in KCNH1 were found to be affected by epilepsy (without association to TBS), while children born with germline mutations from mosaic probands were affected by TBS.[12] This provides further evidence of the role that geneticmosaicism plays in the etiology of neurological disorders.
Type 1Zimmermann–Laband syndrome was later found to be caused by similar missense mutations inKCNH1.[13] This has led some researchers to believe that type 1 Zimmermann-Laband and Temple-Baraitser syndromes are different manifestations of the same disorder.[14][15] Current views are that Zimmermann-Laband and Temple-Baraitser syndromes are part of the greater spectrum ofKCNH1-related disorders, which encompass a continuum of severity for mild to severe developmental delay, profound intellectual disability, neonatal hypotonia, myopathic facial appearance, and infantile-onset seizures.[16]
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.[17] Individuals with missense mutations in KCNH1 have not reported any increase in incidence of cancers.
^Gabbett MT, Clark RC, McGaughran JM (February 2008). "A second case of severe mental retardation and absent nails of hallux and pollex (Temple-Baraitser syndrome)".American Journal of Medical Genetics. Part A.146A (4):450–452.doi:10.1002/ajmg.a.32129.PMID18203178.S2CID2532859.
^abSimons C, Rash LD, Crawford J, Ma L, Cristofori-Armstrong B, Miller D, et al. (January 2015). "Mutations in the voltage-gated potassium channel gene KCNH1 cause Temple-Baraitser syndrome and epilepsy".Nature Genetics.47 (1):73–77.doi:10.1038/ng.3153.PMID25420144.S2CID52799681.
^Kortüm F, Caputo V, Bauer CK, Stella L, Ciolfi A, Alawi M, et al. (June 2015). "Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome".Nature Genetics.47 (6):661–667.doi:10.1038/ng.3282.hdl:2108/118197.PMID25915598.S2CID12060592.
Farias LM, Ocaña DB, Díaz L, Larrea F, Avila-Chávez E, Cadena A, et al. (October 2004). "Ether a go-go potassium channels as human cervical cancer markers".Cancer Research.64 (19):6996–7001.doi:10.1158/0008-5472.CAN-04-1204.PMID15466192.S2CID6791131.
Kang J, Chen XL, Wang H, Ji J, Cheng H, Incardona J, et al. (March 2005). "Discovery of a small molecule activator of the human ether-a-go-go-related gene (HERG) cardiac K+ channel".Molecular Pharmacology.67 (3):827–836.doi:10.1124/mol.104.006577.PMID15548764.S2CID35049797.
Ziechner U, Schönherr R, Born AK, Gavrilova-Ruch O, Glaser RW, Malesevic M, et al. (March 2006). "Inhibition of human ether à go-go potassium channels by Ca2+/calmodulin binding to the cytosolic N- and C-termini".The FEBS Journal.273 (5):1074–1086.doi:10.1111/j.1742-4658.2006.05134.x.PMID16478480.S2CID26926041.
Simons C, Rash LD, Crawford J, Ma L, Cristofori-Armstrong B, Miller D, et al. (January 2015). "Mutations in the voltage-gated potassium channel gene KCNH1 cause Temple-Baraitser syndrome and epilepsy".Nature Genetics.47 (1):73–77.doi:10.1038/ng.3153.PMID25420144.S2CID52799681.
