KCNH1 Membrane Protein Introduction

Introduction of KCNH1

KCNH1, also known as H-Eag, HEAG1, EAG1, EAG, TMBTS, ZLS1, Ether-a-go-go, Drosophila, homolog of KV10.1, or potassium channel, voltage-gated Eag related subfamily H, member 1, is a transmembrane protein of 111.4 k Da and comprises 678 amino acids. In humans, it is encoded by the KCNH1 gene which is located on the chromosome 1q32.2. KCNH1 was originally termed ether à go-go (Eag) as its mutation in Drosophila melanogaster induced a rhythmic leg-shaking phenotype under ether anesthesia. This protein is expressed in different regions of central nervous systems, such as the hippocampus. KCNH1 contains tetrameric α subunits and each subunit consists of 6 membrane-spanning α-helices (S1-S6), of which S1-S4 segments work as voltage sensor domains, and S5, S6 form a pore-lining loop.

Function of KCNH1 Membrane Protein

KCNH1, as voltage-gated potassium (Kv) channel, has the canonical tetrameric structure and six-transmembrane domain topology. In humans, at least 12 (Kv) subfamilies (Kv1 to Kv12) contribute to neuronal signaling in nervous systems. In mammals, the expression of KCNH1 is almost completely limited to the brain, but no specific neuronal function yet is described. Thus far, the only physiological effect ascribed to the vertebrate KCNH1 channel is a promoting role at the onset of myoblast fusion. KCNH channels are essential regulators of cellular excitability and reported to be correlated with cancer, epilepsy, schizophrenia, and cardiac long QT syndrome type 2. An important pathophysiological impact for KCNH1 in the cancer formation has been proposed since the human KCNH1 gene is overexpressed in a broad spectrum of cancers and the channel inhibition can reduce cell proliferation. Additionally, a recent study revealed that missense mutations in KCNH1 cause deleterious gain of function, leading to a multisystem developmental disorder Temple-Baraitser syndrome (TBS).

Fig.1 The membrane topology and domain structure of a single Kcnh1 subunit. (Stengel, 2012)

Application of KCNH1 Membrane Protein in Literature

1. Niday Z and Tzingounis A.V. Potassium Channel Gain of Function in Epilepsy: An Unresolved Paradox. Neuroscientist. 2018, 24(4): 368-380. PubMed ID: 29542386
   
   

   The article describes the current state of the field in regard of the gain-of-function potassium channel variants related to epilepsy (KCNT1, KCNA2, KCNB1, KCND2, KCNH1, KCNH5, KCNJ10, KCNMA1, KCNQ2, and KCNQ3) and speculated on possible mechanisms behind the development of seizures and epilepsy in patients.

2. Mastrangelo M., et al. Epilepsy in KCNH1-related syndromes. Epileptic Disord. 2016, 18(2): 123-136. PubMed ID: 27267311
   
   

   KCNH1 mutations have been identified in patients with Temple-Baraitser syndrome and Zimmermann-Laband syndrome, and patients with indefinite syndromes with intellectual disability and overlapping characteristics. Epilepsy is a critical phenotypic feature in a large number of individuals with KCNH1-related syndromes, advising a direct role of KCNH1 in epileptogenesis.

3. Fukai R., et al. De novo KCNH1 mutations in four patients with syndromic developmental delay, hypotonia and seizures. J Hum Genet. 2016, 61(5): 381-387. PubMed ID: 26818738
   
   

   De novo missense mutations of KCNH1 have recently been identified in 6 patients with Zimmermann-Laband syndrome and in 4 patients with Temple-Baraitser syndrome. This report confirms that KCNH1 mutations are related to the syndromic neurodevelopmental disorder, and also supported the functional importance of the S4 domain.

4. Kortüm F., et al. Mutations in KCNH1 and ATP6V1B2 cause Zimmermann-Laband syndrome. Nat Genet. 2016, 47(6): 661-667. PubMed ID: 25915598
   
   

   Zimmermann-Laband syndrome (ZLS) is a developmental disorder and this study reported that heterozygous missense mutations in KCNH1 are responsible for a considerable proportion of ZLS. The findings indicate that KCNH1 mutations result in ZLS and document genetic heterogeneity for this type of disorder.

5. Simons C., et al. Mutations in the voltage-gated potassium channel gene KCNH1 cause Temple-Baraitser syndrome and epilepsy. Nat Genet. 2015, 47(1): 73-77. PubMed ID: 25420144
   
   

   The article discoveries that two mothers of children with Temple-Baraitser syndrome (TBS), who have epilepsy but healthy, are low-level (10% and 27%) mosaic carriers of pathogenic KCNH1 mutations. Consistent with current reports, this result demonstrates that the etiology of lots of unresolved CNS disorders may be explained by pathogenic mosaic mutations.

KCNH1 Preparation Options

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Reference

1. Stengel R, et al. (2012). Kcnh1 voltage-gated potassium channels are essential for early zebrafish development. J Biol Chem. 287(42): 35565-35575.

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