KCNA2

Official Full Name

potassium voltage-gated channel subfamily A member 2

Organism

Homo sapiens

GeneID

3737

Background

Potassium channels represent the most complex class of voltage-gated ion channels from both functional and structural standpoints. Their diverse functions include regulating neurotransmitter release, heart rate, insulin secretion, neuronal excitability, epithelial electrolyte transport, smooth muscle contraction, and cell volume. Four sequence-related potassium channel genes - shaker, shaw, shab, and shal - have been identified in Drosophila, and each has been shown to have human homolog(s). This gene encodes a member of the potassium channel, voltage-gated, shaker-related subfamily. This member contains six membrane-spanning domains with a shaker-type repeat in the fourth segment. It belongs to the delayed rectifier class, members of which allow nerve cells to efficiently repolarize following an action potential. The coding region of this gene is intronless, and the gene is clustered with genes KCNA3 and KCNA10 on chromosome 1. [provided by RefSeq, Jul 2008]

Synonyms

HK4; MK2; HBK5; NGK1; RBK2; DEE32; HUKIV; KV1.2; EIEE32;

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Detailed Information

Recent Research

The KCNA2 gene belongs to the Kv1 family of voltage-gated potassium channels that are expressed in the central nervous system. The Kv1 channel is present in all eukaryotic cells, and their functions include maintaining membrane potential, regulating cell volume, and modulating electrical excitability in neurons. It plays an essential role in neuronal excitability, as well as seizures susceptibility, and neurotransmitter release.

KCNA2 participates in a growing list of voltage-gated potassium channel genes associated with epileptic encephalopathy, including KCNQ2, KCNQ3, KCNT1 and KCNB1. In fact, Kv1.2 contributes to repolarization of the neuronal membrane following an action potential. Mutations of KCNA2 that interfere with normal Kv1.2 function lead to damage to electrical signals and changes in membrane excitability. Loss-of-function mutation predicted damage to membrane repolarization, resulting in neuronal hyperexcitability and a propensity for repetitive firing. Consistent with this, complete absence of Kv1.2 in homozygous mice resulted in spontaneous seizures and premature death, and heterozygous deletion resulted in increased seizure susceptibility. Mutations are also identified, showing a gain effect of function. In level of a single neuron, the observed effects predict Kv1.2 channels that are open at resting membrane potentials, resulting in neuronal hypoexcitability. However, based on the more severe phenotype of the patients, the net effect within neuronal networks is hyperexcitability. Additional studies will be required to determine the effect of KCNA2 mutations at the level of the network.

So far, phenotypes associated with KCNA2 mutations were divided into two groups according to age of onset, seizure semiology, and electroclinical features. These unique clinical phenotypes appear to be associated with different effects of mutations on protein function. Patients with functional acquired mutations have more severe phenotypes and do not achieve seizure freedom. In contrast, patients with loss-of-function mutations have later seizure onset, and achieve seizure freedom in childhood. This nascent genotype-phenotype correlation is reminiscent of KCNQ2-associated epileptic encephalopathy, where loss-of- function mutations are associated with neonatal onset, while gain-of-function mutations are associated with infantile onset.

In addition, gain-of-function and dominant-negative mutations in KCNA2 have been implicated in early-onset epileptic encephalopathies, ataxia or intellectual disability. KCNA2 mutation can cause dominantly inherited episodic ataxia and generalized and focal epilepsies in the setting of normal intellect. KCNA2, at both transcriptional and translational levels in the injured dorsal root ganglion (DRG), which participates in neuropathic pain genesis DNA methylation, one type of epigenetic modification, represses gene expression. Moreover, KCNA2, coding for voltage-gated potassium channels, is important for sleep regulation across species.

References:

Kearney J A. KCNA2-Related Epileptic Encephalopathy. Pediatric Neurology Briefs, 2015, 29(4):27-27.
Helbig K L, et al. A recurrent mutation in KCNA2 as a novel cause of hereditary spastic paraplegia and ataxia. Annals of Neurology, 2016, 80(4):n/a-n/a.
Zhao J Y, et al. DNA methyltransferase DNMT3a contributes to neuropathic pain by repressing Kcna2 in primary afferent neurons. Nature Communications, 2017, 8:14712.
Hundallah K, et al. Severe early-onset epileptic encephalopathy due to mutations in the KCNA2 gene: Expansion of the genotypic and phenotypic spectrum. European Journal of Paediatric Neurology, 2016, 20(4):657-660.

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