Alternative titles; symbols
HGNC Approved Gene Symbol: ATP6V1B1
Cytogenetic location: 2p13.3 Genomic coordinates (GRCh38): 2:70,935,900-70,965,431 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 2p13.3 | Distal renal tubular acidosis 2 with progressive sensorineural hearing loss | 267300 | Autosomal recessive | 3 |
ATP6B1 encodes a component of vacuolar ATPase (V-ATPase), a multisubunit enzyme that mediates acidification of intracellular organelles. The encoded protein is one of 2 B-subunit isoforms contained within the catalytic domain. H(+)-transporting ATPases are ubiquitous in nature; V-ATPases pump protons against an electrochemical gradient, whereas F-ATPases reverse the process, synthesizing ATP. The 8 or 9 polypeptides that represent subunits of ATP-driven proton pumps associated with the clathrin-coated vesicles and synaptic vesicles are numbered in order of descending apparent molecular mass (Xie and Stone, 1986).
Sudhof et al. (1989) cloned the B1 isoform by screening a human kidney cDNA library with probes designed from the amino acid sequence of the bovine homolog. The deduced 513-amino acid protein has a calculated molecular mass of 56.7 kD. Nelson et al. (1992) noted that the B1 and B2 (606939) isoforms show a high degree of conservation in the internal region of the protein, but diverge at the N- and C-termini. By Northern blot analysis, van Hille et al. (1994) found abundant expression of a 2-kb ATP6B1 transcript in kidney, intermediate expression in placenta, and no expression in pancreas, muscle, liver, lung, brain, or heart.
By study of appropriate interspecific somatic cell hybrids, Ozcelik et al. (1991) mapped the gene for the 58-kD subunit (VPP3) to human chromosome 2 and mouse chromosome 8. By study of hybrid cells with various fragments of chromosome 2, they demonstrated that the VPP3 gene is located in 2cen-q13. By analysis of recombinant inbred strains, they showed that in mice Vpp3 is closely linked to Lpl (238600), which is on mouse chromosome 8 and human chromosome 8.
Karet et al. (1999) mapped the human ATP6B1 gene to the centromeric region of chromosome 2 by radiation hybrid mapping and by linkage using intragenic variants.
Karet et al. (1999) demonstrated that mutations in the ATP6B1 gene, encoding the B subunit of the apical proton pump mediating distal nephron acid secretion, cause distal renal tubular acidosis associated with progressive sensorineural hearing loss (DRTA2; 267300). The sensorineural hearing loss is consistent with the demonstration by Karet et al. (1999) that ATP6B1 is expressed in the cochlea and endolymphatic sac. Active proton secretion is required to maintain proper endolymph pH and normal auditory function. ATP6B1 was the first member of the H(+)-ATPase gene family in which mutations were shown to cause human disease.
Using SSCP of all coding regions and intron-exon boundaries of the ATP6B1 gene, Karet et al. (1999) identified mutations in 19 of 62 kindreds with distal renal tubular acidosis associated with sensorineural deafness (10 recessive and 9 sporadic). There were 15 different mutations that introduced premature termination codons, frameshift mutations, splice site mutations, or nonconservative missense substitutions. Affected individuals were homozygous for the mutations in all except 1 sporadic case which was compound heterozygous.
In a consanguineous Turkish kindred, a brother manifested osteopetrosis and distal RTA (see CA2 deficiency, 259730), whereas his sister manifested only distal RTA and developed sensorineural deafness. Borthwick et al. (2003) excluded defects in the CA2 gene and found instead penetrance of 2 separate recessive disorders, each affecting a different, tissue-specific subunit of the vacuolar proton pump H(+)-ATPase. The osteopetrosis was the result of a homozygous deletion in the TCIRG1 gene (604592.0007), which encodes an osteoclast-specific isoform of subunit A of H(+)-ATPase, whereas the distal RTA was associated with a homozygous mutation in the ATP6V1B1 gene (192132.0005). Borthwick et al. (2003) concluded that coinheritance of 2 rare recessive disorders created a phenocopy of CA2 deficiency in this kindred.
In 3 unrelated kindreds with distal renal tubular acidosis with progressive sensorineural hearing loss (DRTA2; 267300) from Turkey and Spain, Karet et al. (1999) found a change in codon 31 of the ATP6B1 gene converting CGA (arg) to TGA (stop). The mutation (R31X) was homozygous in each instance.
In a male in whom the diagnosis of distal renal tubular acidosis with deafness (DRTA2; 267300) had been made at the age of 1 month, Karet et al. (1999) found a deletion of 1 basepair (a C) from codon 166 (ACG) causing a frameshift and a premature termination at codon 174 of the ATP6B1 gene.
In a male in whom the diagnosis of distal renal tubular acidosis with deafness (DRTA2; 267300) had been made at the age of 5 months, Karet et al. (1999) found homozygosity for a splice site mutation in the ATP6B1 gene.
In a female in whom the diagnosis of renal tubular acidosis with deafness (DRTA2; 267300) had been made at the age of 2 years, Karet et al. (1999) found a leu81-to-pro (L81P) missense mutation in the ATP6B1 gene in homozygous state.
Mohebbi et al. (2013) identified the L81P mutation in 2 unrelated families from Kosovo with renal tubular acidosis with deafness, suggesting that this mutation may be more common in this region. One patient carried the mutation in homozygosity, whereas the other carried it in compound heterozygous state with another pathogenic ATP6V1B1 mutation.
In a brother and sister from a consanguineous Turkish kindred who manifested distal renal tubular acidosis and deafness (DRTA2; 267300), Borthwick et al. (2003) identified a homozygous G-to-A transition in the ATP6V1B1 gene, resulting in a gly78-to-arg (G78R) substitution. Both unaffected parents were heterozygous for the mutation. The brother also had osteopetrosis (259700) due to a concurrent homozygous deletion in the TCIRG1 gene (604592.0007).
In 12 patients with distal renal tubular acidosis and deafness (DRTA2; 267300) from Antioquia, Colombia, Nikali et al. (2008) identified a homozygous G-to-C transversion in intron 12 of the ATP6V1B1 gene, predicted to result in exon skipping and disruption of the C-terminal ATP synthase domain. The mutation was not found in 92 control chromosomes, and haplotype analysis was consistent with a founder effect. Antioquia is a historically isolated population in northwestern Colombia that was established in the 16th to 17th century by an admixture mainly of Native Americans and Spanish immigrants.
Borthwick, K. J., Kandemir, N., Topaloglu, R., Kornak, U., Bakkaloglu, A., Yordam, N., Ozen, S., Mocan, H., Shah, G. N., Sly, W. S., Karet, F. E. A phenocopy of CAII deficiency: a novel genetic explanation for inherited infantile osteopetrosis with distal renal tubular acidosis. J. Med. Genet. 40: 115-121, 2003. [PubMed: 12566520] [Full Text: https://doi.org/10.1136/jmg.40.2.115]
Karet, F. E., Finberg, K. E., Nelson, R. D., Nayir, A., Mocan, H., Sanjad, S. A, Rodriguez-Soriano, J., Santos, F., Cremers, C. W. R. J., DiPietro, A., Hoffbrand, B. I., Winiarski, J., Bakkaloglu, A., Ozen, S., Dusunsel, R., Goodyer, P., Hulton, S. A., Wu, D. K., Skvorak, A. B., Morton, C. C., Cunningham, M. J., Jha, V., Lifton, R. P. Mutations in the gene encoding B1 subunit of H(+)-ATPase cause renal tubular acidosis with sensorineural deafness. Nature Genet. 21: 84-90, 1999. [PubMed: 9916796] [Full Text: https://doi.org/10.1038/5022]
Mohebbi, N., Vargas-Poussou, R., Hegemann, S. C. A., Schuknecht, B., Kistler, A. D., Wuthrich, R. P., Wagner, C. A. Homozygous and compound heterozygous mutations in the ATP6V1B1 gene in patients with renal tubular acidosis and sensorineural hearing loss. Clin. Genet. 83: 274-278, 2013. [PubMed: 22509993] [Full Text: https://doi.org/10.1111/j.1399-0004.2012.01891.x]
Nelson, R. D., Guo, X.-L., Masood, K., Brown, D., Kalkbrenner, M., Gluck, S. Selectively amplified expression of an isoform of the vacuolar H(+)-ATPase 56-kilodalton subunit in renal intercalated cells. Proc. Nat. Acad. Sci. 89: 3541-3545, 1992. [PubMed: 1373501] [Full Text: https://doi.org/10.1073/pnas.89.8.3541]
Nikali, K., Vanegas, J. J., Burley, M.-W., Martinez, J., Lopez, L. M., Bedoya, G., Wrong, O. M., Povey, S., Unwin, R. J., Ruiz-Linares, A. Extensive founder effect for distal renal tubular acidosis (dRTA) with sensorineural deafness in an isolated South American population. (Letter) Am. J. Med. Genet. 146A: 2709-2712, 2008. [PubMed: 18798332] [Full Text: https://doi.org/10.1002/ajmg.a.32495]
Ozcelik, T., Suedhof, T. C., Francke, U. Chromosomal assignments of genes for vacuolar (endomembrane) proton pump subunits VPP1/Vpp-1 (116 kDa) and VPP3/Vpp-3 (58 kDa) in human and mouse. (Abstract) Cytogenet. Cell Genet. 58: 2008-2009, 1991.
Sudhof, T. C., Fried, V. A., Stone, D. K., Johnston, P. A., Xie, X.-S. Human endomembrane H+ pump strongly resembles the ATP-synthetase of Archaebacteria. Proc. Nat. Acad. Sci. 86: 6067-6071, 1989. [PubMed: 2527371] [Full Text: https://doi.org/10.1073/pnas.86.16.6067]
van Hille, B., Richener, H., Schmid, P., Puettner, I., Green, J. R., Bilbe, G. Heterogeneity of vacuolar H(+)-ATPase: differential expression of two human subunit B isoforms. Biochem. J. 303: 191-198, 1994. [PubMed: 7945239] [Full Text: https://doi.org/10.1042/bj3030191]
Xie, X. S., Stone, D. K. Isolation and reconstitution of the clathrin-coated vesicle proton translocating complex. J. Biol. Chem. 261: 2492-2495, 1986. [PubMed: 2869030]