KCNH1

Potassium voltage-gated channel subfamily H member 1 (K_V10.1, EAG1) is an ion channel protein that in humans is encoded by the KCNH1 gene.^{[5] [6] [7]} Disease-causing (pathogenic) mutations in the KCNH1 gene cause KCNH1-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 of KCNH1 is associated with tumor progression.

Expression of KCNH1 is predominantly restricted to the adult central nervous system.^[8] 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.^[9]

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.^[7]

KCNH1 expression is activated in cilia at the onset of myoblast differentiation and known to play roles in the cell cycle and cell proliferation.^[10]

Gabbett and colleagues described Temple–Baraitser syndrome (TBS) in 2008, naming the condition after English clinical 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 that de novo missense mutations in the KCNH1 gene cause deleterious gain of function in the voltage-gated potassium channel K_V10.1, resulting in TBS.^[12] 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.^[12] 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.^[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 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.^[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.

KCNH1 has been shown to interact with KCNB1 ^[18] and is inhibited by the highly-conserved secondary messenger calmodulin in the presence of calcium.

• Voltage-gated potassium channel
• Voltage-gated ion channel
• Channelopathy
• HERG
• KCNH1-related disorders

• KCNH1+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Kv10.1+Potassium+Channel at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
• Human Disease Genes - KCNH1

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

• Genes on human chromosome 1
• PAS-domain-containing proteins

• Articles with short description
• Short description matches Wikidata
• CS1 maint: DOI inactive as of July 2025
• Wikipedia articles incorporating text from the United States National Library of Medicine