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ATP6V0A4
ATPase H+ transporting V0 subunit a4
The ATP6V0A4 gene provides instructions for a vital component of a proton pump essential for maintaining proper acid-base balance in the kidneys and inner ear. ATP6V0A4 encodes a subunit of the vacuolar H+-ATPase (V-ATPase), a protein complex that transports hydrogen ions across membranes.
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 contains instructions for producing part of a large protein complex known as vacuolar H+-ATPase (V-ATPase). This complex acts as a pump, moving positively charged hydrogen ions, or protons, across cellular membranes. This process is fundamental for regulating the relative acidity (pH) within cells and their surrounding environments, which is vital for numerous biological processes.
The V-ATPase that includes the ATP6V0A4 gene product is particularly important in the kidneys and inner ear. In the kidneys, it plays a role in filtering waste and maintaining proper acid levels in the blood and urine. In the inner ear, it contributes to maintaining the correct pH of the fluid called endolymph, which is essential for hearing.
What the gene does
The ATP6V0A4 gene product is a subunit of the vacuolar H+-ATPase (V-ATPase), a complex molecular machine responsible for proton transport. V-ATPases are found in various cell types, where they contribute to the acidification of organelles such as lysosomes and endosomes, and to pH regulation across plasma membranes. The specific V-ATPase containing the ATP6V0A4 subunit is critical for extracellular pH balance.
In the kidneys, this V-ATPase helps to remove excess acid from the blood, facilitating its excretion into the urine. This action is carried out within the renal tubules, which are responsible for reabsorbing necessary substances and eliminating waste. In the inner ear, the V-ATPase helps to maintain the precise pH of the endolymph fluid, a critical factor for the proper functioning of auditory hair cells and therefore for hearing. Impaired function of this proton pump due to ATP6V0A4 variants can disrupt these delicate pH balances, leading to disease.
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Chromosome location
The ATP6V0A4 gene is located on chromosome 7, specifically at position 7q34. This chromosomal location indicates its precise address within the human genome.
Protein structure
The ATP6V0A4 protein is composed of 840 amino acids. While extensive domain architecture details are not fully characterised, a specific disordered region has been identified between amino acids 675 and 704.
Key variants
Variants within the ATP6V0A4 gene can lead to alterations in the protein's structure or function, impacting the efficiency of the V-ATPase proton pump. These genetic changes can impair the kidney's ability to regulate acid-base balance and affect the inner ear's pH, leading to various health conditions. Such variants are typically inherited in an autosomal recessive manner.
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.154_157del | p.Val52fs | Pathogenic | ★★☆☆ | ATP6V0A4-related disorder |
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 | ★★☆☆ | ATP6V0A4-related disorder |
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
Variants in the ATP6V0A4 gene are primarily associated with Renal tubular acidosis type I (ATP6V0A4). This condition involves an impaired ability of the kidneys to excrete acid, leading to an excess of acid in the blood (metabolic acidosis). Depending on the specific variant, individuals may also experience sensorineural hearing loss, which can manifest at different ages.
- 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 included in several NHS Genomic Medicine Service national test panels. These include panels for Nephrocalcinosis or nephrolithiasis (R256) and Renal tubulopathies (R198), indicating its recognised role in these conditions within the UK clinical genetics framework.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What is the main 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 levels. This is particularly important in the kidneys for acid excretion and in the inner ear for maintaining proper fluid balance essential for hearing.
How are conditions related to ATP6V0A4 variants inherited?
Conditions associated with ATP6V0A4 gene variants, such as renal tubular acidosis type I, are typically inherited in an autosomal recessive pattern. This means an individual must inherit two copies of the altered gene, one from each parent, to develop the condition.
Can ATP6V0A4 variants affect hearing?
Yes, ATP6V0A4 gene variants can lead to sensorineural hearing loss. This is because the protein encoded by ATP6V0A4 is involved in maintaining the proper pH of the fluid within the inner ear, which is crucial for normal auditory function.
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