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ATP6V0A2
ATPase H+ transporting V0 subunit a2
The ATP6V0A2 gene encodes a subunit of a proton pump crucial for maintaining cellular pH, protein glycosylation, and vesicle trafficking. The ATP6V0A2 gene provides instructions for making the a2 subunit of the vacuolar H+-ATPase (V-ATPase) protein complex.
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 plays a critical role in cellular function by providing instructions for a component of a large protein complex called vacuolar H+-ATPase (V-ATPase). This enzyme acts as a proton pump, essential for regulating pH within cells and specific cellular compartments like endosomes and lysosomes. Proper pH control is fundamental for numerous biological processes, including the proper functioning of proteins and cellular metabolism.
Disruptions to the ATP6V0A2 gene can impact these vital functions, leading to a range of health conditions. Its involvement in glycosylation, a process where sugar molecules are added to proteins, further highlights its importance in cellular health and development.
What the gene does
The ATP6V0A2 gene is responsible for producing the a2 subunit of the vacuolar H+-ATPase (V-ATPase) protein complex. V-ATPases function as proton pumps, actively transporting positively charged hydrogen atoms (protons) across cellular membranes. This movement is crucial for regulating the relative acidity (pH) of both the cell's interior and its surrounding environment. Maintaining precise pH levels is essential for most biological reactions to occur correctly.
Within cells, V-ATPases are key in managing the pH of specific compartments, such as endosomes and lysosomes, which are involved in breaking down and recycling cellular waste. Evidence suggests these pumps also contribute to the movement of vesicles, which are small sacs that transport molecules throughout the cell. Furthermore, V-ATPases are integral to glycosylation, a complex process where proteins are modified by adding sugar molecules. This modification is necessary for many proteins to function properly, and V-ATPases regulate the pH of the Golgi apparatus, where glycosylation primarily takes place.
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Chromosome location
The ATP6V0A2 gene is situated on chromosome 12 at position 12q24.31. This genomic location specifies the precise address of the gene within the human genome, aiding in its identification and study.
Protein structure
The ATP6V0A2 gene codes for a protein that is 856 amino acids long. This protein functions as the a2 subunit of the vacuolar H+-ATPase (V-ATPase) complex. Domain architecture has not been experimentally characterised in detail for this protein.
Key variants
Variants within the ATP6V0A2 gene can disrupt its normal function, potentially leading to altered protein structure or reduced protein activity. These changes can impair the V-ATPase complex's ability to regulate pH and facilitate glycosylation, contributing to the development of associated health conditions. Over 40 different variants in this gene have been identified in individuals with specific 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.1062dup | p.Ser355fs | Pathogenic | ★★☆☆ | ALG9 congenital disorder of glycosylation |
c.130del | p.Asn43_Val44insTer | Pathogenic | ★★☆☆ | Wrinkly skin syndrome |
c.1514+1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Wrinkly skin syndrome |
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 primarily associated with Cutis laxa type 2A. This is an autosomal recessive condition characterised by loose, sagging skin and distinct facial features. Other features often include larger than normal spaces between skull bones, known as fontanelles, which may close later than typically expected. The impact of these variants on the V-ATPase complex underlies the diverse symptoms observed in affected individuals.
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 included in several expert-curated NHS Genomic Medicine Service national panels. It is listed with a 'green' status for conditions such as Congenital disorders of glycosylation, Early onset or syndromic epilepsy, Ehlers Danlos syndrome with a likely monogenic cause (R101), Foetal anomalies (R21), Intellectual disability, Likely inborn error of metabolism (R98), Skeletal dysplasia (R104), and Undiagnosed metabolic disorders.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the ATP6V0A2 gene?
The ATP6V0A2 gene provides instructions for making a component of the vacuolar H+-ATPase (V-ATPase) protein complex, which acts as a proton pump to regulate cellular pH and is involved in protein glycosylation and vesicle trafficking.
What condition is most commonly associated with variants in ATP6V0A2?
Variants in the ATP6V0A2 gene are primarily associated with Cutis laxa type 2A, an autosomal recessive disorder characterised by loose skin and distinctive facial features.
Is ATP6V0A2 included in any NHS genetic testing panels?
Yes, ATP6V0A2 is part of several NHS Genomic Medicine Service panels, including those for congenital disorders of glycosylation, early onset or syndromic epilepsy, and skeletal dysplasia.
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