Alternative titles; symbols
HGNC Approved Gene Symbol: ATP6V0A4
Cytogenetic location: 7q34 Genomic coordinates (GRCh38) : 7:138,706,294-138,798,196 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 7q34 | Distal renal tubular acidosis 3, with or without sensorineural hearing loss | 602722 | Autosomal recessive | 3 |
Vacuolar-type proton pumps help maintain acid-base homeostasis either within intracellular compartments or at specialized plasma membranes. The pumps are made up of 13 subunits, which form 2 functional domains: a V1 domain where ATP hydrolysis provides energy for proton movement, and a membrane-anchored V0 domain where proton translocation takes place. ATP6V0A4 is 1 of the subunits that form the V0 domain (Golder and Karet Frankl, 2016).
By candidate gene sequencing with the critical interval on chromosome 7q33-q34 that had been established for a form of autosomal recessive distal renal tubular acidosis (DRTA3; 602722) by Karet et al. (1999), Smith et al. (2000) identified the ATP6N1B gene. ATP6N1B encodes a deduced 840-amino acid, 116-kD kidney-specific isoform of the H(+)-ATPase vacuolar proton pump. The ATP6N1B protein shares 61% and 47% amino acid identity, respectively, with the other human 116-kD subunits ATP6N1A (ATP6V0A1; 192130) and OC116 (TCIRG1; 604592) and approximately 60% identity with the rat, bovine, and mouse 116-kD subunits. Like its homologs, ATP6N1B is predicted to have a 2-domain structure. The N-terminal half is hydrophilic and likely intracellular, whereas the C-terminal half is composed of 6 putative transmembrane domains with a short intracellular C terminus. Northern blot analysis demonstrated a 3.3-kb ATP6N1B transcript solely in adult and fetal kidney. Immunofluorescence studies in human kidney cortex showed that ATP6N1B localized almost exclusively to the apical surface of alpha-intercalated cells.
Stover et al. (2002) found ATP6V0A4 expression within the cochlea of both fetal and adult tissue specimens.
Using LacZ reporter analysis, Golder and Karet Frankl (2016) demonstrated that Atp6v0a4 was expressed with Atp6v1c2 (618070) and Atp6v0d2 (618072) in mouse olfactory epithelium and embryonic visceral yolk sac. Atp6v0a4 was also expressed in ampullary gland, prostatic alveoli, and uterus.
The ATP6N1B gene contains 23 exons and encodes 3 alternatively spliced isoforms (Smith et al., 2000).
Smith et al. (2000) identified the ATP6N1B gene on chromosome 7q33-q34.
In affected members of 8 of 9 kindreds with renal tubular acidosis with normal audiometry linked to chromosome 7q33-q34 (DRTA3; 602722), Smith et al. (2000) identified homozygous mutations in the ATP6N1B gene (605239.0001-605239.0008). These included nonsense, deletion, and splice site changes, all of which were predicted to truncate the protein. The findings illustrated the essential role of ATP6N1B in normal vectorial acid transport into the urine by the kidney.
In 12 kindreds with autosomal recessive distal renal tubular acidosis and 11 sporadic cases of dRTA, Stover et al. (2002) identified 19 ATP6V0A4 mutations (see, e.g., 605239.0009-605239.0010) in 23 patients. Several of these patients, including 1 with a previously identified splice site mutation (605239.0003), were found to have developed later onset of hearing loss than occurs in dRTA families with progressive sensorineural hearing loss (267000) and mutations in the ATP6V1B1 gene (192132). Review of a previously studied ATP6V0A4 cohort revealed 1 patient who had developed mild sensorineural hearing loss at the age of 22.
Vargas-Poussou et al. (2006) found that 9 of 23 patients with DRTA3 had sensorineural hearing loss; in 2 patients the age at onset was unknown, but in the other 7, hearing loss was detected between ages 2 months and 10 years (see, e.g., 605239.0011). Additionally, 12 other patients were younger than age 10 years and could yet develop hearing loss.
Norgett et al. (2012) found that Atp6v0a4 -/- mice were born at the expected mendelian ratio and were fertile. However, they were smaller at 2 to 3 weeks of age compared with wildtype, and most demonstrated a likely inner ear defect and did not survive weaning. Those Atp6v0a4 -/- mice that survived weaning typically died suddenly and did not live beyond 6 months. Histologic analysis showed kidney defects in the surviving mice. Unweaned Atp6v0a4 -/- mice were acidotic but retained normal excretory renal function, even though they were dehydrated. Atp6v0a4 -/- mice lacked auditory brainstem responses (ABR), indicating severe hearing impairment. Most Atp6v0a4 -/- mice survived if treated with alkalinized water. Histologic analysis revealed tubular vacuolation in Atp6v0a4 -/- mice, but not in wildtype or Atp6v0a4 +/- mice or in Atp6v0a4 -/- mice treated with alkalinized water. Olfactory behavioral testing suggested hyposmia in Atp6v0a4 -/- mice. Norgett et al. (2012) concluded that the phenotype of Atp6v0a4 -/- mice resembles human DRTA3 to a greater extent than that of Atp6v1b1 -/- mice, possibly due to the use of a pure C57BL6/J background for Atp6v0a4 -/- mice compared with a mixed background for Atp6v1b1 -/- mice.
Lorente-Canovas et al. (2013) showed that ABRs had significantly elevated thresholds in Atp6v0a4 -/- mice, whereas Atp6v0a4 +/- mice were normal. Inner ears in Atp6v0a4 -/- mice had a marked expansion of cochlear and endolymphatic ducts. Atp6v0a4 -/- mice also lacked endocochlear potential, suggesting a functional defect of the stria vascularis on the lateral wall of the cochlear duct. However, the main potassium channels involved in generation of the potential, Kcnj10 (602208) and Kcnq1 (607542), were strongly expressed in Atp6v0a4 -/- mice. Lorente-Canovas et al. (2013) concluded that ATP6V0A4 has an important role in hearing function.
In a study of 1,751 knockout alleles created by the International Mouse Phenotyping Consortium (IMPC), Dickinson et al. (2016) found that knockout of the mouse homolog of human ATP6V0A4 is homozygous-lethal (defined as absence of homozygous mice after screening of at least 28 pups before weaning).
In a 6.5-year-old Turkish child in whom the diagnosis of distal renal tubular acidosis (DRTA3; 602722) had been made at the age of 3 weeks, Smith et al. (2000) found a homozygous glu753-to-ter (Q753X) nonsense mutation in the ATP6N1B gene. Audiometry at the age of 4.5 years was normal. A C-to-T transition introduced the premature termination codon.
In a 10-year-old child with distal renal tubular acidosis with normal hearing (DRTA3; 602722), Smith et al. (2000) identified a gly820-to-arg (G820R) missense mutation in the ATP6N1B gene. Renal tubular acidosis had been diagnosed at the age of 1 year.
In a 22-year-old Pakistani female with distal renal tubular acidosis with normal hearing (DRTA3; 602722), Smith et al. (2000) identified a mutation in the consensus donor splice site of intron 17 of the ATP6N1B gene. Renal tubular acidosis had been diagnosed at the age of 1 week.
In an 18-year-old Pakistani woman (kindred 25) with dRTA and late-onset sensorineural hearing loss, Stover et al. (2002) identified the IVS17+1G-A mutation in the ATP6V0A4 gene.
In a 14-year-old Turkish female with distal renal acidosis (DRTA3; 602722), Smith et al. (2000) found a 1-bp deletion in codon 35 (valine) of the ATP6N1B gene causing a frameshift, altering the following protein sequence and ending in premature termination at codon 40. Renal acidosis was diagnosed at the age of 3 months; audiometry was normal at 12 years.
In a 4-year-old Turkish boy with distal renal tubular acidosis and normal hearing (DRTA3; 602722), Smith et al. (2000) found an met580-to-thr missense mutation in the ATP6N1B gene.
In an 11-year-old Turkish girl with distal renal tubular acidosis and normal hearing (DRTA3; 602722), Smith et al. (2000) identified a change in the canonical acceptor splice sequence in intron 6 of the ATP6N1B gene from AG to AA.
In a 13-year-old Saudi Arabian male with distal renal tubular acidosis and presumably normal hearing (DRTA3; 602722), Smith et al. (2000) identified deletion of 1 bp in codon 276 of the ATP6N1B gene (glutamine) resulting in frameshift and premature termination.
In a 3-year-old Turkish male with distal renal tubular acidosis and normal hearing (DRTA3; 602722), Smith et al. (2000) identified a pro524-to-leu missense mutation in the ATP6N1B gene.
In a 34-year-old Spanish man (kindred 72) with distal renal tubular acidosis (DRTA3; 602722), Stover et al. (2002) identified a c.1506T-A transversion in the ATP6V0A4 gene, resulting in a tyr502-to-stop (Y502X) mutation. This mutation was found to be frequent in patients from northern Spain, suggesting founder effect. The patient was found to have sensorineural hearing loss for the first time at the age of 33 years. He had had previous audiograms within normal limits.
In a 26-year-old Spanish man (kindred 70) with distal renal tubular acidosis (DRTA3; 602722), Stover et al. (2002) identified a c.2420G-A transition in the ATP6V0A4 gene, resulting in an arg807-to-gln (R807Q) mutation. The diagnosis of renal tubular acidosis was made at the age of 2 months. The patient had severe hearing loss requiring the use of hearing aids.
In a 15-year-old Algerian girl with distal renal tubular acidosis and sensorineural hearing loss (DRTA2; 602722), Vargas-Poussou et al. (2006) identified a homozygous 1-bp deletion (c.2137delG, NM_130841) in the ATP6V0A4 gene, resulting in a frameshift and a premature termination codon (Glu713fsTer765). She was diagnosed with renal tubular acidosis at age 1 week and with hearing loss at age 6 years.
Dickinson, M. E., Flenniken, A. M., Ji, X., Teboul, L., Wong, M. D., White, J. K., Meehan, T. F., Weninger, W. J., Westerberg, H., Adissu, H., Baker, C. N., Bower, L., and 73 others. High-throughput discovery of novel developmental phenotypes. Nature 537: 508-514, 2016. Note: Erratum: Nature 551: 398 only, 2017. [PubMed: 27626380] [Full Text: https://doi.org/10.1038/nature19356]
Golder, Z. J., Karet Frankl, F. E. Extra-renal locations of the a4 subunit of H(+)ATPase. BMC Cell Biol. 17: 27, 2016. Note: Electronic Article. [PubMed: 27368196] [Full Text: https://doi.org/10.1186/s12860-016-0106-8]
Karet, F. E., Finberg, K. E., Nayir, A., Bakkaloglu, A., Ozen, S., Hulton, S. A., Sanjad, S. A., Al-Sabban, E. A., Medina, J. F., Lifton, R. P. Localization of a gene for autosomal recessive distal renal tubular acidosis with normal hearing (rdRTA2) to 7q33-34. Am. J. Hum. Genet. 65: 1656-1665, 1999. [PubMed: 10577919] [Full Text: https://doi.org/10.1086/302679]
Lorente-Canovas, B., Ingham, N., Norgett, E. E., Golder, Z. J., Karet Frankl, F. E., Steel, K. P. Mice deficient in H(+)-ATPase a4 subunit have severe hearing impairment associated with enlarged endolymphatic compartments within the inner ear. Dis. Model Mech. 6: 434-442, 2013. [PubMed: 23065636] [Full Text: https://doi.org/10.1242/dmm.010645]
Norgett, E. E., Golder, Z. J., Lorente-Canovas, B., Ingham, N., Steel, K. P., Karet Frankl, F. E. Atp6v0a4 knockout mouse is a model of distal renal tubular acidosis with hearing loss, with additional extrarenal phenotype. Proc. Nat. Acad. Sci. 109: 13775-13780, 2012. [PubMed: 22872862] [Full Text: https://doi.org/10.1073/pnas.1204257109]
Smith, A. N., Skaug, J., Choate, K. A., Nayir, A., Bakkaloglu, A., Ozen, S., Hulton, S. A., Sanjad, S. A., Al-Sabban, E. A., Lifton, R. P., Scherer, S. W., Karet, F. E. Mutations in ATP6N1B, encoding a new kidney vacuolar proton pump 116-kD subunit, cause recessive distal renal tubular acidosis with preserved hearing. Nature Genet. 26: 71-75, 2000. [PubMed: 10973252] [Full Text: https://doi.org/10.1038/79208]
Stover, E. H., Borthwick, K. J., Bavalia, C., Eady, N., Fritz, D. M., Rungroj, N., Giersch, A. B. S., Morton, C. C., Axon, P. R., Akil, I., Al-Sabban, E. A., Baguley, D. M., and 20 others. Novel ATP6V1B1 and ATP6V0A4 mutations in autosomal recessive distal renal tubular acidosis with new evidence for hearing loss. J. Med. Genet. 39: 796-803, 2002. [PubMed: 12414817] [Full Text: https://doi.org/10.1136/jmg.39.11.796]
Vargas-Poussou, R., Houillier, P., Le Pottier, N., Stompf, L., Loirat, C., Baudouin, V., Macher, M.-A., Dechaux, M., Ulinski, T., Nobili, F., Eckart, P., Novo, R., and 15 others. Genetic investigation of autosomal recessive distal renal tubular acidosis: evidence for early sensorineural hearing loss associated with mutations in the ATP6V0A4 gene. J. Am. Soc. Nephrol. 17: 1437-1443, 2006. [PubMed: 16611712] [Full Text: https://doi.org/10.1681/ASN.2005121305]