KCNH1

Function

Expression of KCNH1 is predominantly restricted to the adult central nervous system. The KCNH1 gene encodes a homotetrameric highly-conserved voltage-gated potassium channel (KV10.1) thought to be responsible for reestablishing the membrane potential of excitatory neurons in response to high frequency firing.

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 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 in cilia at the onset of myoblast differentiation and known to play roles in the cell cycle and cell proliferation.

Pathologies

[[KCNH1-related disorders]]

Gabbett and colleagues described Temple–Baraitser syndrome (TBS) in 2008, naming the condition after English clinical geneticists Profs Karen Temple and Michael Baraitser. 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 KV10.1, resulting in TBS. Patients with de 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. 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. This has led some researchers to believe that type 1 Zimmermann-Laband and Temple-Baraitser syndromes are different manifestations of the same disorder. Current views are that Zimmermann-Laband and Temple-Baraitser syndromes are part of the greater spectrum of KCNH1-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.

KCNH1 in cancer

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. Individuals with missense mutations in KCNH1 have not reported any increase in incidence of cancers.

Interactions

KCNH1 has been shown to interact with KCNB1 and is inhibited by the highly-conserved secondary messenger calmodulin in the presence of calcium.

References

References

1. (August 1998). "Cloning of a human ether-a-go-go potassium channel expressed in myoblasts at the onset of fusion". FEBS Letters.
2. (December 2005). "International Union of Pharmacology. LIII. Nomenclature and molecular relationships of voltage-gated potassium channels". Pharmacological Reviews.
3. "Entrez Gene: KCNH1 potassium voltage-gated channel, subfamily H (eag-related), member 1".
4. "603305 - Potassium channel, voltage-gated; subfamily H, member 1; KCNH1". Online Mendelian Inheritance in Man (OMIM).
5. (2015). "KV10.1 opposes activity-dependent increase in Ca2+ influx into the presynaptic terminal of the parallel fibre–Purkinje cell synapse". The Journal of Physiology.
6. (1999-10-15). "Oncogenic potential of EAG K+ channels". The EMBO Journal.
7. (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.
8. (January 2015). "Mutations in the voltage-gated potassium channel gene KCNH1 cause Temple-Baraitser syndrome and epilepsy". Nature Genetics.
9. (June 2015). "Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome". Nature Genetics.
10. (June 2016). "Temple-Baraitser Syndrome and Zimmermann-Laband Syndrome: one clinical entity?". BMC Medical Genetics.
11. (October 2015). "'Splitting versus lumping': Temple-Baraitser and Zimmermann-Laband Syndromes". Human Genetics.
12. (September 2025). "The molecular basis of KCNH1-related epileptic encephalopathy and the challenge of developing targeted therapeutics". Brain.
13. (2014-03-19). "Potassium channels in cell cycle and cell proliferation". Philosophical Transactions of the Royal Society of London. Series B, Biological Sciences.
14. (June 2002). "Obligatory heterotetramerization of three previously uncharacterized Kv channel alpha-subunits identified in the human genome". Proceedings of the National Academy of Sciences of the United States of America.