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ATP6V0A4
ATPase H+ transporting V0 subunit a4
The ATP6V0A4 gene provides instructions for a vital component of a proton pump involved in maintaining the body's acid-base balance, particularly in the kidneys and inner ear. The ATP6V0A4 gene is essential for producing a subunit of the vacuolar H+-ATPase (V-ATPase) complex.
ATP6V0A4 is located on the long (q) arm of chromosome 7, at band 7q34. Arm ratio per GRCh38 - banding schematic.
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Overview
The ATP6V0A4 gene encodes a subunit of a large protein complex called vacuolar H+-ATPase (V-ATPase). This complex functions as a proton pump, moving positively charged hydrogen atoms across cellular membranes. This movement is fundamental to regulating pH levels, which is crucial for numerous biological processes throughout the body.
The V-ATPase containing the ATP6V0A4 subunit is primarily found in the kidneys and the inner ear. In the kidneys, it is instrumental in filtering waste products and regulating the amount of acid excreted into the urine. In the inner ear, it helps maintain the correct pH of the fluid known as endolymph. Disruptions to this gene's function can therefore impact kidney function and hearing.
What the gene does
The ATP6V0A4 gene provides instructions for creating a component of the vacuolar H+-ATPase (V-ATPase) protein complex. V-ATPases are proton pumps responsible for actively transporting hydrogen ions (protons) across biological membranes. This process is essential for acidifying various cellular compartments and regulating the pH of extracellular fluids.
Specifically, the V-ATPase complex containing the ATP6V0A4 subunit is critical in the kidneys. Here, it facilitates the removal of excess acid from the blood into the urine, maintaining the body's systemic acid-base balance. Within the inner ear, this particular V-ATPase helps to sustain the precise pH environment of the endolymph, which is vital for normal auditory function. Proper pH control is indispensable for the efficient operation of most biochemical reactions and overall physiological homeostasis.
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Chromosome location
The ATP6V0A4 gene is situated on chromosome 7, specifically at position 7q34. This location refers to the long (q) arm of chromosome 7, band 34.
Protein structure
The protein encoded by the ATP6V0A4 gene consists of 840 amino acids. Its structural composition includes a notable disordered region spanning amino acids 675 to 704. This region may contribute to the protein's flexibility or its interactions with other molecules.
Key variants
Genetic variations within the ATP6V0A4 gene can lead to altered protein function. These variations, often referred to as pathogenic or likely pathogenic variants, can impair the ability of the V-ATPase proton pump to transport hydrogen ions effectively. The specific type and location of a variant can influence the severity and presentation of associated 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.1107del | p.Asn370fs | Pathogenic | ★★☆☆ | Renal tubular acidosis, distal, 3, with or without sensorineural hearing loss |
c.1185del | p.Tyr396fs | Pathogenic | ★★☆☆ | Renal tubular acidosis, distal, 3, with or without sensorineural hearing loss |
c.1187dup | p.Tyr396Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Renal tubular acidosis, distal, 3, with or without sensorineural hearing loss |
c.1345C>T | p.Arg449Cys | Pathogenic/Likely pathogenic | ★★☆☆ | Renal tubular acidosis, distal, 3, with or without sensorineural hearing loss |
c.1478+2T>G | - | Pathogenic/Likely pathogenic | ★★☆☆ | Renal tubular acidosis, distal, 3, with or without sensorineural hearing loss |
c.16C>T | p.Arg6Ter | Pathogenic | ★★☆☆ | Renal tubular acidosis, distal, 3, with or without sensorineural hearing loss |
c.2257+1G>A | - | Pathogenic | ★★☆☆ | Autosomal recessive distal renal tubular acidosis |
c.292-1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Renal tubular acidosis, distal, 3, with or without sensorineural hearing loss |
c.707AGA[1] | p.Lys237del | Pathogenic/Likely pathogenic | ★★☆☆ | Renal tubular acidosis, distal, 3, with or without sensorineural hearing loss |
c.977G>A | p.Trp326Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Renal tubular acidosis, distal, 3, with or without sensorineural hearing loss |
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 ATP6V0A4 gene are associated with several conditions, most notably Renal tubular acidosis type I (ATP6V0A4). This disorder is characterised by the kidneys' inability to adequately excrete acid, leading to an excess of acid in the blood (metabolic acidosis). It can also be associated with bone weakness and sensorineural hearing loss, which is caused by issues within the inner ear.
- Renal tubular acidosis type I (ATP6V0A4) Dedicated page coming soon
Inheritance pattern
Conditions caused by pathogenic ATP6V0A4 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 ATP6V0A4 gene is recognised in the UK National Health Service (NHS) Genomic Medicine Service. It is listed on PanelApp for conditions such as Nephrocalcinosis or nephrolithiasis (R256) and Renal tubulopathies (R198), both categorised as having 'green' evidence status, indicating strong evidence for gene-disease association.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the primary function of the ATP6V0A4 gene?
The ATP6V0A4 gene provides instructions for a subunit of the vacuolar H+-ATPase (V-ATPase), a proton pump critical for regulating pH in the kidneys and inner ear. This helps maintain the body's acid-base balance and supports normal hearing.
Which medical conditions are associated with ATP6V0A4 gene variants?
Variants in the ATP6V0A4 gene are primarily associated with Renal tubular acidosis type I. This condition involves the kidneys' impaired ability to remove acid, which can lead to metabolic acidosis, bone issues, and sometimes sensorineural hearing loss.
How does ATP6V0A4 relate to kidney function?
In the kidneys, the protein produced from the ATP6V0A4 gene is part of a pump that helps move hydrogen ions into the urine. This process is crucial for eliminating excess acid from the blood and maintaining the body's proper acid-base balance.
References
- Li X, Chai Y, Tao Z. Novel mutations in ATP6V0A4 are associated with atypical progressive sensorineural hearing loss in a Chinese patient with distal renal tubular acidosis. International journal of pediatric otorhinolaryngology. 2012. PMID: 22093743
- Batlle D, Haque SK. Genetic causes and mechanisms of distal renal tubular acidosis. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association. 2012. PMID: 23114896
- Alper SL. Familial renal tubular acidosis. Journal of nephrology. 2010. PMID: 21170890
- Andreucci E, Bianchi B, Carboni I. Inner ear abnormalities in four patients with dRTA and SNHL: clinical and genetic heterogeneity. Pediatric nephrology (Berlin, Germany). 2009. PMID: 19639346
- Vargas-Poussou R, Houillier P, Le Pottier N. Genetic investigation of autosomal recessive distal renal tubular acidosis: evidence for early sensorineural hearing loss associated with mutations in the ATP6V0A4 gene. Journal of the American Society of Nephrology : JASN. 2006. PMID: 16611712
- Stover EH, Borthwick KJ, Bavalia C. Novel ATP6V1B1 and ATP6V0A4 mutations in autosomal recessive distal renal tubular acidosis with new evidence for hearing loss. Journal of medical genetics. 2002. PMID: 12414817