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ATP6V0A2
ATPase H+ transporting V0 subunit a2
The ATP6V0A2 gene provides instructions for a component of a vital enzyme complex, the vacuolar H+-ATPase (V-ATPase), which is crucial for cellular pH regulation and protein modification. The ATP6V0A2 gene is responsible for producing the a2 subunit of the vacuolar H+-ATPase, an enzyme complex that helps maintain proper pH levels within cells and their compartments.
ATP6V0A2 is located on the long (q) arm of chromosome 12, at band 12q24.31. Arm ratio per GRCh38 - banding schematic.
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Overview
The ATP6V0A2 gene, also known as ATPase H+ transporting V0 subunit a2, plays a fundamental role in human biology by encoding a subunit of the vacuolar H+-ATPase (V-ATPase) protein complex. This complex acts as a proton pump, essential for regulating the acidity (pH) within cells and their specialised compartments. Proper pH control is vital for numerous biological reactions and cellular functions.
Dysfunction of the ATP6V0A2 gene can lead to disruptions in these critical cellular processes. Inherited variants in this gene are associated with specific health conditions, highlighting its importance in maintaining normal physiological function.
What the gene does
The ATP6V0A2 gene provides the blueprint for the a2 subunit, a key component of the large V-ATPase protein complex. This enzyme complex functions as a proton pump, actively transporting positively charged hydrogen atoms (protons) across cell membranes. By moving protons, V-ATPases contribute to maintaining the precise pH balance within cells and their surrounding environments.
Within the cell, V-ATPases are integral to regulating the pH of organelles such as endosomes and lysosomes, which are responsible for the digestion and recycling of cellular waste. Evidence suggests these pumps are also involved in the trafficking of vesicles, which transport molecules throughout the cell. Additionally, V-ATPases play a significant role in glycosylation, a complex process where sugar molecules are added to proteins. This modification, which occurs in the Golgi apparatus, is necessary for many proteins to function correctly, and V-ATPases regulate the Golgi's pH, directly impacting glycosylation.
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Chromosome location
The ATP6V0A2 gene is situated on chromosome 12, specifically at position 12q24.31. This genomic address specifies the precise location of the gene on the long (q) arm of chromosome 12.
Protein structure
The ATP6V0A2 gene encodes a protein composed of 856 amino acids. This protein is identified as the a2 subunit of the vacuolar H+-ATPase. Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Variants in the ATP6V0A2 gene can alter the protein's structure or function, potentially impairing the activity of the V-ATPase complex. Such changes can disrupt cellular pH regulation, glycosylation, and other vital processes. The impact of specific variants can vary, leading to a range of clinical presentations.
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.1062dup | p.Ser355fs | Pathogenic | ★★☆☆ | ALG9 congenital disorder of glycosylation |
c.130del | p.Asn43_Val44insTer | Pathogenic/Likely pathogenic | ★★☆☆ | Wrinkly skin syndrome |
c.1514+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | ATP6V0A2-related disorder |
c.1576C>T | p.Arg526Ter | Pathogenic | ★★☆☆ | ALG9 congenital disorder of glycosylation |
c.187C>T | p.Arg63Ter | Pathogenic | ★★☆☆ | Cutis laxa |
c.208C>T | p.Gln70Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Wrinkly skin syndrome |
c.2293C>T | p.Gln765Ter | Pathogenic | ★★☆☆ | ALG9 congenital disorder of glycosylation |
c.304C>T | p.Gln102Ter | Pathogenic | ★★☆☆ | not provided |
c.390_397dup | p.Arg133delinsThrCysTer | Pathogenic | ★★☆☆ | Cutis laxa with osteodystrophy |
c.732-2A>G | - | Pathogenic | ★★☆☆ | ALG9 congenital disorder of glycosylation |
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 ATP6V0A2 gene are associated with specific inherited conditions. Most notably, these variants are a cause of Cutis laxa type 2A, an autosomal recessive disorder. This condition is characterised by features such as loose, sagging skin, distinctive facial characteristics, and delayed closure of the skull's fontanelles.
Inheritance pattern
Conditions caused by pathogenic ATP6V0A2 variants typically follow autosomal recessive inheritance.
When both parents are carriers, each child has a 25% chance of being affected, 50% of being a carrier, and 25% of being unaffected.
UK clinical status
The ATP6V0A2 gene is recognised within several NHS Genomic Medicine Service national panels in the UK, indicating its clinical relevance for diagnostic testing. It is currently part of panels for Congenital disorders of glycosylation, Early onset or syndromic epilepsy, Ehlers Danlos syndrome with a likely monogenic cause, Foetal anomalies, Intellectual disability, Likely inborn error of metabolism, Skeletal dysplasia, and Undiagnosed metabolic disorders.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main function of the ATP6V0A2 gene?
The ATP6V0A2 gene provides instructions for making a subunit of the vacuolar H+-ATPase (V-ATPase) complex. This complex is crucial for regulating the pH within cells and their compartments, which is essential for processes like protein glycosylation.
Which condition is primarily associated with ATP6V0A2 gene variants?
Variants in the ATP6V0A2 gene are primarily associated with Cutis laxa type 2A, an inherited disorder characterised by distinctive skin and skeletal features.
How does the ATP6V0A2 gene affect protein modification?
The ATP6V0A2 gene, through its role in the V-ATPase complex, helps regulate the pH of the Golgi apparatus. This pH regulation is critical for glycosylation, a process where sugar molecules are added to proteins, which is necessary for their proper function.
References
- Guillard M, Dimopoulou A, Fischer B. Vacuolar H+-ATPase meets glycosylation in patients with cutis laxa. Biochimica et biophysica acta. 2009. PMID: 19171192
- Hucthagowder V, Morava E, Kornak U. Loss-of-function mutations in ATP6V0A2 impair vesicular trafficking, tropoelastin secretion and cell survival. Human molecular genetics. 2009. PMID: 19321599
- Morava E, Lefeber DJ, Urban Z. Defining the phenotype in an autosomal recessive cutis laxa syndrome with a combined congenital defect of glycosylation. European journal of human genetics : EJHG. 2008. PMID: 17971833
- Kornak U, Reynders E, Dimopoulou A. Impaired glycosylation and cutis laxa caused by mutations in the vesicular H+-ATPase subunit ATP6V0A2. Nature genetics. 2008. PMID: 18157129
- Marshansky V, Futai M. The V-type H+-ATPase in vesicular trafficking: targeting, regulation and function. Current opinion in cell biology. 2008. PMID: 18511251
- Marshansky V. The V-ATPase a2-subunit as a putative endosomal pH-sensor. Biochemical Society transactions. 2007. PMID: 17956287