On this page
ATP1A2
ATPase Na+/K+ transporting subunit alpha 2
The ATP1A2 gene provides instructions for a crucial component of the Na+/K+ ATPase, a protein vital for nerve cell function and the regulation of ion balance in the brain. The ATP1A2 gene codes for the alpha-2 subunit of the Na+/K+ ATPase, an enzyme that pumps sodium ions out of and potassium ions into cells.
ATP1A2 is located on the long (q) arm of chromosome 1, at band 1q23.2. Arm ratio per GRCh38 - banding schematic.
Explore chromosome 1 in the library →Available at Jeen Health
Clinical tests that include this
Overview
The ATP1A2 gene, also known as ATPase Na+/K+ transporting subunit alpha 2, plays a fundamental role in maintaining cellular health, particularly within the nervous system. It encodes a specific subunit of the Na+/K+ ATPase protein, an ion pump critical for establishing and maintaining electrochemical gradients across cell membranes. Proper function of this protein is essential for nerve impulse transmission and overall brain activity.
Disruptions in the ATP1A2 gene can lead to a range of neurological disorders, highlighting its significance in central nervous system physiology. These conditions often involve disturbances in ion balance and neuronal excitability.
What the gene does
The ATP1A2 gene directs the synthesis of the alpha-2 subunit, which is one part of the Na+/K+ ATPase protein. This enzyme acts as an active transporter, utilising energy derived from adenosine triphosphate (ATP) to move ions across cell membranes. Specifically, it actively pumps three sodium ions (Na+) out of the cell for every two potassium ions (K+) it pumps into the cell.
Within the nervous system, Na+/K+ ATPases containing the alpha-2 subunit are predominantly found in glial cells. Glial cells are support cells that surround and protect neurons. Here, the protein is crucial for regulating the extracellular environment around neurons, clearing neurotransmitters from the synaptic cleft, and removing excess potassium ions. This meticulous regulation is fundamental for accurate signal transmission between neurons, ensuring the proper functioning of the entire nervous system.
Video: Genetics 101
Chromosome location
The ATP1A2 gene is situated on chromosome 1, specifically at position 1q23.2. This genomic location describes its precise address on the long arm of chromosome 1. The gene provides the blueprint for a protein consisting of 1020 amino acids.
Protein structure
The ATP1A2 protein is 1020 amino acids long. Its structural organisation includes a disordered region spanning amino acids 1 to 31 at the N-terminus. There is also a specific region between amino acids 80 and 82 that is involved in interaction with phosphoinositide-3 kinase. Another disordered region is found between amino acids 212 and 231.
Key variants
Variants within the ATP1A2 gene can affect the structure and function of the Na+/K+ ATPase protein, leading to a spectrum of neurological conditions. These genetic changes can range from single amino acid substitutions to larger alterations that impair the protein's ability to transport ions effectively or to interact with other cellular components. The specific variant often dictates the resulting clinical presentation and severity.
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.1234C>T | p.Arg412Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Fetal akinesia, respiratory insufficiency, microcephaly, polymicrogyria, and dysmorphic facies |
c.1453A>T | p.Lys485Ter | Pathogenic | ★★☆☆ | Familial hemiplegic migraine |
c.1477C>T | p.Arg493Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Familial hemiplegic migraine |
c.1639del | p.Glu547fs | Pathogenic | ★★☆☆ | Familial hemiplegic migraine |
c.1642C>T | p.Arg548Cys | Pathogenic | ★★☆☆ | Familial hemiplegic migraine |
c.1810C>T | p.Arg604Ter | Pathogenic | ★★☆☆ | Familial hemiplegic migraine |
c.1843G>A | p.Gly615Arg | Pathogenic/Likely pathogenic | ★★☆☆ | Familial hemiplegic migraine |
c.2501G>A | p.Arg834Gln | Pathogenic/Likely pathogenic | ★★☆☆ | ATP1A2-related disorder |
c.2723G>A | p.Arg908Gln | Pathogenic/Likely pathogenic | ★★☆☆ | ATP1A2-related disorder |
c.3027T>A | p.Tyr1009Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Familial hemiplegic migraine |
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
Variants in the ATP1A2 gene are associated with several inherited neurological conditions. These include familial hemiplegic migraine type 2 (FHM2), a severe form of migraine characterised by temporary weakness on one side of the body. ATP1A2 variants also contribute to sporadic hemiplegic migraine, which presents similarly but without a clear family history, and alternating hemiplegia of childhood, a condition marked by recurrent episodes of temporary paralysis. Research also suggests an association with general Migraine (Polygenic / Complex).
UK clinical status
The ATP1A2 gene is included in several active 'green' panels within the NHS Genomic Medicine Service's PanelApp, indicating that there is strong evidence for its association with specific conditions and that it is routinely analysed in a diagnostic setting in the UK. These panels cover a broad range of neurological and developmental disorders, including Arthrogryposis, Brain channelopathy, Dystonia, chorea or related movement disorder (both adult and childhood onset), Early onset or syndromic epilepsy, Familial cerebral small vessel disease, Foetal anomalies, Hereditary ataxia (adult onset), Intellectual disability, Malformations of cortical development, Paroxysmal central nervous system disorders, Severe microcephaly, and Skeletal Muscle Channelopathies. It is also part of the DDG2P (Deciphering Developmental Disorders) panel.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the ATP1A2 gene do?
The ATP1A2 gene provides instructions for making the alpha-2 subunit of the Na+/K+ ATPase protein. This protein is an ion pump that moves sodium ions out of cells and potassium ions into cells, a process critical for nerve cell function and maintaining proper electrical balance in the brain.
What conditions are associated with ATP1A2 gene variants?
Variants in the ATP1A2 gene are associated with several neurological conditions, including familial hemiplegic migraine type 2, sporadic hemiplegic migraine, and alternating hemiplegia of childhood. These conditions typically involve disturbances in nervous system function.
How does ATP1A2 affect brain function?
The ATP1A2 gene's product helps regulate ion concentrations, particularly in glial cells surrounding neurons. This regulation is essential for clearing neurotransmitters and excess potassium ions from the spaces between nerve cells, which is vital for accurate communication and signal transmission throughout the nervous system.
References
- Riant F, Ducros A, Ploton C. De novo mutations in ATP1A2 and CACNA1A are frequent in early-onset sporadic hemiplegic migraine. Neurology. 2010. PMID: 20837964
- Tavraz NN, Dürr KL, Koenderink JB. Impaired plasma membrane targeting or protein stability by certain ATP1A2 mutations identified in sporadic or familial hemiplegic migraine. Channels (Austin, Tex.). 2009. PMID: 19372756
- Castro MJ, Nunes B, de Vries B. Two novel functional mutations in the Na+,K+-ATPase alpha2-subunit ATP1A2 gene in patients with familial hemiplegic migraine and associated neurological phenotypes. Clinical genetics. 2008. PMID: 18028456
- Pietrobon D. Familial hemiplegic migraine. Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics. 2007. PMID: 17395138
- de Vries B, Freilinger T, Vanmolkot KR. Systematic analysis of three FHM genes in 39 sporadic patients with hemiplegic migraine. Neurology. 2007. PMID: 18056581
- Riant F, De Fusco M, Aridon P. ATP1A2 mutations in 11 families with familial hemiplegic migraine. Human mutation. 2005. PMID: 16088919
- Jurkat-Rott K, Freilinger T, Dreier JP. Variability of familial hemiplegic migraine with novel A1A2 Na+/K+-ATPase variants. Neurology. 2004. PMID: 15159495
- Swoboda KJ, Kanavakis E, Xaidara A. Alternating hemiplegia of childhood or familial hemiplegic migraine? A novel ATP1A2 mutation. Annals of neurology. 2004. PMID: 15174025
- Bassi MT, Bresolin N, Tonelli A. A novel mutation in the ATP1A2 gene causes alternating hemiplegia of childhood. Journal of medical genetics. 2004. PMID: 15286158