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ATP13A2
ATPase cation transporting 13A2
ATP13A2 is located on the short (p) arm of chromosome 1, at band 1p36.13. Arm ratio per GRCh38 - banding schematic.
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Overview
ATP13A2 (ATPase cation transporting 13A2) is located on chromosome 1 and encodes a member of the P-type ATPase family of transport proteins. These enzymes use energy from ATP to move ions across cellular membranes, maintaining the chemical gradients essential for cell survival and function.
The ATP13A2 protein operates primarily within lysosomes, the cellular compartments responsible for breaking down and recycling cellular materials. By regulating metal ion concentrations in these organelles, ATP13A2 helps protect neurons from toxic metal accumulation and supports normal lysosomal function. When this gene carries pathogenic variants, the resulting protein dysfunction can lead to progressive neurological conditions affecting movement, cognition, and other nervous system functions.
What the gene does
The ATP13A2 protein functions as a cation pump that transports positively charged metal ions across lysosomal membranes. Research suggests this protein plays a particularly important role in managing zinc, manganese, and potentially other divalent cations within cellular compartments.
Within lysosomes, ATP13A2 helps maintain the acidic environment needed for proper enzyme function and cargo degradation. The protein appears to protect cells from metal-induced toxicity by pumping excess cations out of the lysosomal lumen into the cytoplasm, where they can be safely managed or exported from the cell.
Evidence indicates that ATP13A2 contributes to cellular processes beyond simple ion transport. The protein supports autophagy, the cellular recycling pathway that clears damaged organelles and protein aggregates. It also appears involved in maintaining mitochondrial health and protecting neurons from oxidative stress. Loss of ATP13A2 function leads to lysosomal dysfunction, accumulation of undegraded materials, and progressive cellular damage, particularly in neurons that are highly sensitive to disruptions in metal homeostasis.
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Chromosome location
ATP13A2 is located on the short arm of chromosome 1 at position p36.13, a region near the chromosome's terminal end. This chromosomal band contains numerous genes, and structural variations affecting 1p36 can impact multiple genetic loci simultaneously.
The gene spans a genomic region that encodes the information needed to produce the full-length 1,180-amino-acid protein through transcription and translation processes.
Protein structure
Domain architecture has not been experimentally characterised in detail for this protein. However, as a member of the P5B subfamily of P-type ATPases, ATP13A2 is predicted to contain the characteristic structural features of this enzyme family, including transmembrane segments that span the lysosomal membrane and cytoplasmic regions that bind and hydrolyse ATP to power ion transport. The protein's 1,180-amino-acid length suggests a complex structure with multiple functional regions coordinating the energy-dependent movement of cations across membranes.
Key variants
Pathogenic variants in ATP13A2 typically result in loss of protein function through various mechanisms, including premature protein truncation, misfolding, or impaired catalytic activity. The inheritance pattern varies depending on the specific condition; some ATP13A2-related disorders follow autosomal recessive inheritance, whilst others may exhibit more complex patterns. The severity and specific features of associated conditions can differ based on the nature and location of variants within the gene.
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.1033_1034del | p.Leu345fs | Pathogenic | ★★☆☆ | ATP13A2-related disorder |
c.1459C>T | p.Arg487Ter | Pathogenic | ★★☆☆ | Inborn genetic diseases |
c.1657C>T | p.Arg553Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive spastic paraplegia type 78 |
c.2097del | p.Ser700fs | Pathogenic | ★★☆☆ | Neurodegeneration with brain iron accumulation |
c.2116C>T | p.Gln706Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive spastic paraplegia type 78 |
c.2135_2136del | p.Val712fs | Pathogenic/Likely pathogenic | ★★☆☆ | Kufor-Rakeb syndrome |
c.2455C>T | p.Arg819Ter | Pathogenic | ★★☆☆ | Kufor-Rakeb syndrome |
c.2529+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive spastic paraplegia type 78 |
c.477+2T>G | - | Pathogenic/Likely pathogenic | ★★☆☆ | Kufor-Rakeb syndrome |
c.604del | p.His202fs | Pathogenic | ★★☆☆ | Inborn genetic diseases |
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
ATP13A2 pathogenic variants are associated with a spectrum of neurological conditions characterised by movement abnormalities, cognitive decline, and nervous system dysfunction. These conditions range from childhood-onset neurodegenerative disorders to adult-onset movement disorders, reflecting the protein's essential role in maintaining neuronal health across the lifespan. The clinical presentations often include features of parkinsonism, dystonia, spasticity, and cognitive impairment, sometimes accompanied by lysosomal storage abnormalities. The wide range of phenotypes reflects both the diverse cellular roles of ATP13A2 and potential genetic and environmental modifying factors that influence disease expression.
No disease links recorded for this gene in our reference set.
UK clinical status
Within the UK NHS Genomic Medicine Service, ATP13A2 holds green classification status across 16 clinical panels, indicating strong evidence supporting its role in hereditary disease. The gene appears on panels for movement disorders including Adult onset dystonia, chorea or related movement disorder (R56) and Childhood onset dystonia, chorea or related movement disorder (R57), as well as Early onset dystonia. It features on both adult and childhood hereditary spastic paraplegia panels (R60 and R61) and neurodegenerative disorder panels (R58). ATP13A2 is also included on specialised panels for Parkinson Disease and Complex Parkinsonism, Lysosomal storage disorder (R276), and Neuronal ceroid lipofuscinosis (R231), reflecting the protein's lysosomal function. Additional memberships include Intellectual disability (R29), Hereditary neuropathy or pain disorder (R78), and metabolic disorder panels (R98 and Undiagnosed metabolic disorders). This extensive panel representation reflects the gene's involvement in multiple overlapping neurological pathways.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What does the ATP13A2 protein do in cells?
ATP13A2 functions as a cation pump in lysosomes, transporting metal ions such as zinc and manganese across membranes to maintain proper cellular ion balance. This activity supports lysosomal function, protects neurons from metal toxicity, and contributes to cellular recycling processes.
What types of conditions are associated with ATP13A2 variants?
Pathogenic ATP13A2 variants are linked to a range of neurological conditions affecting movement and cognition. These include early-onset parkinsonism, dystonia, spastic paraplegia, and neurodegenerative disorders, sometimes with features of lysosomal storage disease.
How is ATP13A2 relevant to UK clinical genetics services?
ATP13A2 holds green status on 16 NHS Genomic Medicine Service panels, including those for movement disorders, parkinsonism, spastic paraplegia, lysosomal storage disorders, and intellectual disability. This classification indicates strong evidence for the gene's role in these conditions and supports its inclusion in relevant clinical genetic testing.