ATP1A1: The Alpha-1 Subunit of the Na+/K+ ATPase
A critical ion pump gene implicated in neurological, cardiovascular, and metabolic disorders
Gene Information Card
| Symbol | ATP1A1 |
|---|---|
| Full Name | ATPase Na+/K+ Transporting Subunit Alpha 1 |
| Gene Type | protein-coding |
| Chromosomal Location | 1p13.1 |
| NCBI Gene ID | 476 ncbi.nlm.nih.gov/gene/476 |
| Ensembl ID | ENSG00000163399 |
| UniProt ID | P05023 |
| OMIM ID | 182310 |
| HGNC ID | 799 |
| Aliases | Na+/K+ ATPase alpha-1 subunit, ATP1A1, MGC3285, MGC51750 |
Description
ATP1A1 encodes the alpha-1 catalytic subunit of the Na+/K+ ATPase, an integral membrane protein responsible for establishing and maintaining the electrochemical gradient of Na+ and K+ ions across the plasma membrane. This enzyme is essential for cellular ion homeostasis, osmotic balance, and secondary active transport of nutrients and neurotransmitters. The alpha-1 isoform is ubiquitously expressed and is the predominant catalytic subunit in most tissues. Mutations in ATP1A1 are associated with several disorders, including Charcot-Marie-Tooth disease, spastic paraplegia, and renal salt-wasting syndromes.
Disease Associations
| Disease category | Pathophysiological mechanism | Genomic evidence |
|---|---|---|
| Charcot-Marie-Tooth disease, axonal, type 2DD | Loss-of-function mutations impair ion transport, leading to peripheral nerve degeneration | ClinVar, OMIM |
| Hereditary spastic paraplegia 89 | Dominant-negative mutations disrupt Na+/K+ ATPase activity in motor neurons | ClinVar, OMIM |
| Renal salt-wasting syndrome | Gain-of-function mutations increase Na+ reabsorption, causing electrolyte imbalance | ClinVar, OMIM |
| Primary aldosteronism | Somatic mutations in adrenal adenomas lead to aldosterone overproduction | COSMIC, OMIM |
Expression Profile
Tissue Expression
| Tissue | nTPM | level |
|---|---|---|
| Brain | 32.5 | High |
| Heart | 28.1 | High |
| Kidney | 45.2 | High |
| Liver | 18.7 | Medium |
| Lung | 22.3 | Medium |
| Skeletal Muscle | 15.4 | Medium |
| Pancreas | 12.8 | Medium |
Cell Line Expression
| Cell Line | nTPM | Notes |
|---|---|---|
| HEK 293 | 35.0 | High expression in embryonic kidney cells |
| HeLa | 28.5 | High expression in cervical cancer cells |
| K562 | 20.1 | Moderate expression in leukemia cells |
| SH-SY5Y | 30.2 | High expression in neuroblastoma cells |
Data source：Human Protein Atlas（proteinatlas.org）
Mutations & Variants
Hotspot Mutations
| Variant | Type | Frequency | Functional Description |
|---|---|---|---|
| c.245G>A (p.Arg82His) | Missense | 0.01% | Loss of function; associated with Charcot-Marie-Tooth disease |
| c.1100T>C (p.Leu367Pro) | Missense | 0.005% | Dominant-negative; linked to spastic paraplegia |
| c.1837C>T (p.Arg613Trp) | Missense | 0.02% | Gain of function; found in primary aldosteronism |
| c.2548G>A (p.Glu850Lys) | Missense | 0.008% | Loss of function; associated with renal salt-wasting |
Mutation functional classification
Loss of Function (LOF)
Mutations that reduce or abolish Na+/K+ ATPase activity, leading to impaired ion homeostasis and neurodegeneration (e.g., p.Arg82His).
Gain of Function (GOF)
Mutations that increase pump activity or alter ion selectivity, causing electrolyte imbalances and aldosterone excess (e.g., p.Arg613Trp).
Dominant Negative (DN)
Mutations that produce a defective alpha-1 subunit that interferes with wild-type function, often seen in spastic paraplegia (e.g., p.Leu367Pro).
View complete mutation data：
Gene Ontology (GO)
Pathways
• REACT:17015 – Na+/K+ ATPase in ion transport
• KEGG:04960 – Aldosterone-regulated sodium reabsorption
• KEGG:04260 – Cardiac muscle contraction
• KEGG:04724 – Glutamatergic synapse
• WikiPathways:WP78 – Ion channel and transporter pathways
Protein Summary
The ATP1A1 protein (UniProt P05023) is a 1023-amino acid multi-pass membrane protein that forms the catalytic alpha-1 subunit of the Na+/K+ ATPase. It contains 10 transmembrane domains and a large cytoplasmic loop with ATP-binding and phosphorylation sites. The protein hydrolyzes ATP to transport 3 Na+ ions out of the cell and 2 K+ ions into the cell per cycle. It is ubiquitously expressed and essential for maintaining resting membrane potential, cell volume, and secondary transport. Post-translational modifications include phosphorylation and palmitoylation, which regulate its activity and localization.
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