On this page
KCNA1
potassium voltage-gated channel subfamily A member 1
The KCNA1 gene provides instructions for a key component of potassium channels, which are vital for electrical signal transmission in the nervous system. KCNA1 encodes a subunit of the Kv1.1 voltage-gated potassium channel, essential for regulating nerve impulses.
KCNA1 is located on the short (p) arm of chromosome 12, at band 12p13.32. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 12 in the library →Overview
The KCNA1 gene, also known as potassium voltage-gated channel subfamily A member 1, is a member of a large gene family involved in forming potassium channels. These channels facilitate the movement of positively charged potassium ions across cell membranes, which is fundamental for generating and transmitting electrical signals within cells.
Specifically, the protein produced from the KCNA1 gene, called Kv1.1, is crucial for nerve cell (neuron) communication, particularly in the brain. The controlled flow of ions, including potassium, into and out of neurons helps regulate their signalling capabilities.
What the gene does
The KCNA1 gene is responsible for creating one part, known as an alpha subunit, of the Kv1.1 potassium channel. These channels are integral membrane proteins found predominantly in the brain, where they enable the transport of potassium ions into nerve cells. This ion movement is critical for the precise regulation of electrical impulses that allow neurons to communicate effectively.
The Kv1.1 channel's activity directly influences the excitability of neurons, playing a role in the timing and frequency of action potentials. Proper channel function is therefore essential for maintaining normal nervous system activity. Disruptions can lead to altered electrical signalling, contributing to various neurological symptoms.
Video: Genetics 101
Chromosome location
The KCNA1 gene is located on chromosome 12, specifically at position 12p13.32. This chromosomal address defines its precise physical location within the human genome. The gene's exact position on the short arm of chromosome 12 is important for genetic mapping and understanding its potential involvement in inherited conditions.
Protein structure
The KCNA1 gene codes for a protein that is 495 amino acids long. This protein contains several functional regions. The Tetramerization domain, spanning amino acids 1-128, is important for the assembly of four alpha subunits into a functional channel. A Disordered region is also present within amino acids 1-30. The S4-S5 linker, located between amino acids 310-323, connects different structural parts of the protein. The Selectivity filter, a critical Motif from amino acids 372-377, ensures that only potassium ions pass through the channel. Finally, a PDZ-binding Motif is found at amino acids 493-495, which typically mediates interactions with scaffolding proteins.
Key variants
Variants in the KCNA1 gene can alter the structure or function of the Kv1.1 potassium channel, affecting its ability to regulate ion flow. These genetic changes can lead to channels that are either overactive or underactive, disrupting the delicate balance of electrical signalling in nerve cells. The specific location and type of variant often determine the severity and manifestation of associated conditions.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.1187G>T | p.Gly396Val | Pathogenic/Likely pathogenic | ★★☆☆ | Episodic kinesigenic dyskinesia |
c.1210G>A | p.Val404Ile | Pathogenic | ★★☆☆ | KCNA1-related disorder |
c.1214C>T | p.Pro405Leu | Pathogenic | ★★☆☆ | Episodic ataxia type 1 |
c.1249C>T | p.Arg417Ter | Pathogenic | ★★☆☆ | Episodic ataxia type 1 |
c.520G>T | p.Val174Phe | Pathogenic | ★★☆☆ | Inborn genetic diseases |
c.677C>G | p.Thr226Arg | Pathogenic | ★★☆☆ | Episodic ataxia type 1 |
c.677C>T | p.Thr226Met | Pathogenic | ★★☆☆ | Episodic ataxia type 1 |
c.745TTC[1] | p.Phe250del | Pathogenic/Likely pathogenic | ★★☆☆ | Inborn genetic diseases |
c.785T>C | p.Ile262Thr | Pathogenic/Likely pathogenic | ★★☆☆ | Episodic ataxia type 1 |
c.847G>A | p.Glu283Lys | Pathogenic | ★★☆☆ | Episodic ataxia type 1 |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Pathogenic variants in the KCNA1 gene are primarily associated with Episodic ataxia type 1 (EA1), an autosomal dominant inherited neurological disorder. Individuals with EA1 typically experience brief, recurrent episodes of poor coordination and balance. Between episodes, many may also exhibit myokymia, which involves involuntary muscle cramping, stiffness, and continuous, fine muscle twitching. KCNA1 variants have also been linked to isolated myokymia and, in some cases, recurrent seizures (epilepsy).
Inheritance pattern
Conditions caused by pathogenic KCNA1 variants typically follow autosomal dominant inheritance.
Each child has a 50% chance of inheriting the pathogenic variant, regardless of sex.
UK clinical status
The KCNA1 gene is currently assessed on several NHS Genomic Medicine Service national panels in the UK. It is categorised as a 'green' gene for various conditions, indicating that there is strong evidence for its association with these conditions and it is routinely included in testing. These include panels for Ataxia and cerebellar anomalies - childhood onset, Brain channelopathy, Dystonia, chorea or related movement disorder (childhood onset, R57), Early onset or syndromic epilepsy, Hereditary ataxia (including adult onset), Paroxysmal central nervous system disorders (R66), and Skeletal Muscle Channelopathies (R76).
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the KCNA1 gene?
The KCNA1 gene provides instructions for creating a component of the Kv1.1 potassium channel. This channel is crucial for regulating the flow of potassium ions into nerve cells, which is essential for normal electrical signalling and communication within the brain.
What conditions are associated with KCNA1 variants?
Variants in the KCNA1 gene are primarily linked to Episodic ataxia type 1 (EA1), a neurological disorder characterised by episodes of poor coordination and balance. Some variants may also be associated with myokymia (continuous muscle twitching) and certain forms of epilepsy.
How do KCNA1 variants affect health?
KCNA1 variants can alter the function of the Kv1.1 potassium channel, leading to abnormal ion flow across nerve cell membranes. This disruption in electrical signalling can impair neuron communication, causing symptoms such as ataxia, muscle twitching, and seizures.
References
- Chen H, von Hehn C, Kaczmarek LK. Functional analysis of a novel potassium channel (KCNA1) mutation in hereditary myokymia. Neurogenetics. 2007. PMID: 17136396
- Rajakulendran S, Schorge S, Kullmann DM. Episodic ataxia type 1: a neuronal potassium channelopathy. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics. 2007. PMID: 17395136
- Jen JC, Graves TD, Hess EJ. Primary episodic ataxias: diagnosis, pathogenesis and treatment. Brain : a journal of neurology. 2007. PMID: 17575281
- Rea R, Spauschus A, Eunson LH. Variable K(+) channel subunit dysfunction in inherited mutations of KCNA1. The Journal of physiology. 2002. PMID: 11773313
- Maylie B, Bissonnette E, Virk M. Episodic ataxia type 1 mutations in the human Kv1.1 potassium channel alter hKvbeta 1-induced N-type inactivation. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2002. PMID: 12077175
- Eunson LH, Rea R, Zuberi SM. Clinical, genetic, and expression studies of mutations in the potassium channel gene KCNA1 reveal new phenotypic variability. Annals of neurology. 2000. PMID: 11026449
- Zerr P, Adelman JP, Maylie J. Episodic ataxia mutations in Kv1.1 alter potassium channel function by dominant negative effects or haploinsufficiency. The Journal of neuroscience : the official journal of the Society for Neuroscience. 1998. PMID: 9526001
- Browne DL, Gancher ST, Nutt JG. Episodic ataxia/myokymia syndrome is associated with point mutations in the human potassium channel gene, KCNA1. Nature genetics. 1994. PMID: 7842011