Alternative titles; symbols
SNOMEDCT: 236532003; ORPHA: 18, 402041;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 2p13.3 | Distal renal tubular acidosis 2 with progressive sensorineural hearing loss | 267300 | Autosomal recessive | 3 | ATP6V1B1 | 192132 |
A number sign (#) is used with this entry because of evidence that distal renal tubular acidosis with progressive sensorineural hearing loss (DRTA2) is caused by homozygous or compound heterozygous mutation in the ATP6V1B1 (ATP6B1) gene (192132) on chromosome 2p13.
Konigsmark (1966) observed a 17-year-old girl who had calculi removed from both kidneys at age 12. Studies at that time showed renal tubular acidosis and bilateral neural deafness. One brother, aged 20, had similar renal disease and progressive nerve deafness. The parents, who were unrelated, and another brother were normal. Nance et al. (1970) observed sibs with this combination of abnormalities. Cohen et al. (1973) described a possibly allelic form with greater severity of both the otologic and the renal defects.
Shapira et al. (1974) found an inactive mutant form of red cell carbonic anhydrase (CA) II (611492) in 2 sisters and a first cousin once removed with renal tubular acidosis and nerve deafness. The parents of both sibships were consanguineous and members of a kindred that had migrated to Israel from a small Jewish community in Kurdistan. The mutant CA II had 7 rather than 8 tyrosine residues, and kinetic studies revealed an extremely low specific activity of the mutant enzyme for the physiologic substrates used, bicarbonate and carbon dioxide. Shapira et al. (1974) suggested that CA II might have a major role in renal tubular acidification and might be the pathogenic basis for the form of RTA observed in this family. However, Tashian et al. (1980) found no abnormality of red cell CA I (114800) or CA II in 1 of the patients originally studied by Shapira et al. (1974).
Dunger et al. (1980) analyzed the urinary acidification and bicarbonate excretion of 2 brothers with RTA and nerve deafness. Their findings suggested that the renal defect in these patients resides in the distal tubule, i.e., is renal tubular acidosis of the classic type I.
Anai et al. (1984) reported a Japanese brother and sister with RTA and nerve deafness in whom carbonic anhydrases I and II in red blood cells were normal. That renal tubular acidosis with deafness is an entity separate from RTA with osteopetrosis (259730) is indicated by the fact that deafness is not a feature of the latter condition and mental retardation and cerebral calcification are not features of the former (Sly, 1989).
Karet et al. (1999) studied the distal renal tubular acidosis syndrome with deafness in 4 outbred kindreds with 2 or more affected sibs and in 27 kindreds with parental consanguinity, of which 7 had more than 1 affected individual. Of the 27 consanguineous kindreds, parents were first cousins in 20 and more distantly related in the remainder. All index cases were diagnosed by 6 years of age, with 19 diagnosed by 1 year of age. They presented either acutely with dehydration and vomiting, or with failure to thrive and/or growth impairment. In each case, the diagnosis was based on inappropriately alkaline urine (pH greater than 5.5) and the presence of systemic metabolic acidosis with normal anion gap, evidence of renal potassium wasting, and no evidence of secondary causes of dRTA. All patients, including infants, had nephrocalcinosis, accompanied by elevated urinary calcium where this was measured. Rickets was also noted in 5 of these kindreds. Despite the nephrocalcinosis, renal function was otherwise normal in every case, and remained so in all but 1 female who developed end-stage renal disease at 18 years of age; the median follow-up was 5 years (range 0.5 to 40). All patients had normal serum sodium, calcium, phosphate, creatinine, and magnesium. Bilateral sensorineural hearing loss was found in 15 affected subjects from 10 kindreds. The hearing loss varied in severity from mild (40 dB) to profound (100 dB). In 20 subjects from 15 kindreds, audiometry excluded a sensorineural deficit. Significantly, hearing status in all 10 tested sib pairs or trios with dRTA was concordant, suggesting that the occurrence of hearing impairment was not stochastic among affected patients.
In 2 Greek Cypriot families with autosomal recessive dRTA and homozygosity and compound heterozygosity for mutations in the ATP6V1B1 gene, respectively, Feldman et al. (2006) reported long-term clinical findings in 4 of 5 affected members. The 5 patients demonstrated the entire clinical spectrum of the disease including death in infancy, failure to thrive, rickets, nephrocalcinosis, nephrolithiasis, and episodes of hypokalemic paralysis. For family members in their third and fourth decades, nephrolithiasis with recurrent colic was their primary problem; renal function remained normal.
Karet et al. (1999) used a genomewide linkage screen to map the gene responsible for dRTA to chromosome 2p. This attracted attention to the ATP6B1 gene, which had been assigned to 2cen-q13. Using radiation hybrid mapping, they demonstrated that ATP6B1 is located in the maximum likelihood interval for dRTA, within 1 cR of D2S292. Subsequent analysis of linkage using intragenic variants of the ATP6B1 gene confirmed this location.
Karet et al. (1999) demonstrated that distal renal tubular acidosis with progressive sensorineural hearing loss is caused by biallelic mutation in the ATP6B1 gene (see 192132.0001-192132.0004), which encodes the B subunit of the apical proton pump mediating distal nephron acid secretion. Consistent with the associated hearing loss, Karet et al. (1999) demonstrated expression of ATP6B1 in the cochlea and endolymphatic sac. This demonstration, together with the known requirement for active proton secretion to maintain proper endolymph pH, implicated ATP6B1 in endolymph pH homeostasis and in normal auditory function.
Stover et al. (2002) investigated 26 new autosomal recessive dRTA kindreds and identified ATP6V0A4 (605239) mutations in 12 kindreds (DRTA3; 602722) and ATP6V1B1 mutations in 10 kindreds; the remaining 4 families (2 with normal audiometry, 1 with sensorineural hearing loss, and 1 of unknown hearing status) were not linked to ATP6V0A4 or ATP6V1B1, providing evidence for additional genetic heterogeneity in dRTA. Several patients with mutations in the ATP6V0A4 gene, including 1 with a previously identified splice site mutation (605239.0003) and 2 with missense mutations (605239.0009-605239.0010), were found to have developed later onset of hearing loss than occurs in dRTA families with progressive sensorineural hearing loss and mutation in the ATP6V1B1 gene. The discovery of late-onset sensorineural hearing loss in some cases of autosomal recessive dRTA, as well as the demonstration that ATP6V0A4 is expressed within the cochlea, suggested that RTA with or without sensorineural hearing loss is the same disorder.
Vargas-Poussou et al. (2006) screened 39 new kindreds with recessive dRTA for mutations in the ATP6V0A4 and ATP6V1B1 genes. Fourteen new and 5 recurrent mutations in the ATP6V0A4 gene were identified in 21 families. Two new and 2 recurrent mutations were detected in the ATP6V1B1 gene in 10 families. No mutation was detected in 8 families. Loss-of-function mutations were found in a total of 31 families, with a global detection rate of 79.5%. Mutations in the ATP6V0A4 gene were twice as frequent as mutations in the ATP6V1B1 gene. The authors noted that this finding conflicts with previous studies, in which mutations in the ATP6V1B1 gene were more frequent than mutations in the ATP6V0A4 gene. Vargas-Poussou et al. (2006) found early-onset hearing loss in 70% of patients with ATP6V1B1 mutations and 39% of patients with ATP6V0A4 mutations. The authors concluded that a genetic screening strategy based on early-onset hearing loss would be misleading and is not recommended.
In a brother and sister from a consanguineous Turkish kindred who manifested distal renal tubular acidosis and deafness, Borthwick et al. (2003) identified homozygosity for a gly78-to-arg substitution in the ATP6V1B1 gene (192132.0005). Because the brother also had osteopetrosis, CA2 deficiency (see 259730) had initially been suspected in this family but was excluded by direct sequencing of the CA2 gene. The osteopetrosis was found to be due to a concurrent homozygous deletion in the TCIRG1 gene (604592.0007). Borthwick et al. (2003) concluded that coinheritance of 2 rare recessive disorders had created a phenocopy of CA2 deficiency in the brother.
Nikali et al. (2008) identified a homozygous mutation in the ATP6V1B1 gene (192132.0006) in 12 patients with distal renal tubular acidosis and deafness from Antioquia, Colombia. Haplotype analysis was consistent with a founder effect. Antioquia is an isolated population in northwestern Colombia that was established in the 16th to 17th century by an admixture mainly of Native Americans and Spanish immigrants.
Reviews
Fry and Karet (2007) reviewed the clinical features and molecular genetics of the inherited renal acidoses.
Anai, T., Yamamoto, J., Matsuda, I., Taniguchi, N., Kondo, T., Nagai, B. Siblings with renal tubular acidosis and nerve deafness: the first family in Japan. Hum. Genet. 66: 282-285, 1984. [PubMed: 6425198] [Full Text: https://doi.org/10.1007/BF00286618]
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]
Cohen, T., Brand-Auraban, A., Karshai, C., Jacob, A., Gay, I., Tsitsianov, J., Shapiro, T., Jatziv, S., Ashkenazi, A. Familial infantile renal tubular acidosis and congenital nerve deafness: an autosomal recessive syndrome. Clin. Genet. 4: 275-278, 1973. [PubMed: 4765211] [Full Text: https://doi.org/10.1111/j.1399-0004.1973.tb01155.x]
Cremers, C. W. R. J., Monnens, L. A. H., Marres, E. H. M. A. Renal tubular acidosis and sensorineural deafness: an autosomal recessive syndrome. Arch. Otolaryng. 106: 287-289, 1980. [PubMed: 6768350] [Full Text: https://doi.org/10.1001/archotol.1980.00790290039013]
Donckerwolcke, R. A., van Biervliet, J. P., Koorevaar, G., Kuijten, R. H., Van Stekelenburg, G. J. The syndrome of renal tubular acidosis with nerve deafness. Acta Paediat. Scand. 65: 100-104, 1976. [PubMed: 1251715] [Full Text: https://doi.org/10.1111/j.1651-2227.1976.tb04414.x]
Dunger, D. B., Brenton, D. P., Cain, A. R. Renal tubular acidosis and nerve deafness. Arch. Dis. Child. 55: 221-225, 1980. [PubMed: 7387165] [Full Text: https://doi.org/10.1136/adc.55.3.221]
Feldman, M., Prikis, M., Athanasiou, Y., Elia, A., Pierides, A., Deltas, C. C. Molecular investigation and long-term clinical progress in Greek Cypriot families with recessive distal renal tubular acidosis and sensorineural deafness due to mutations in the ATP6V1B1 gene. Clin. Genet. 69: 135-144, 2006. [PubMed: 16433694] [Full Text: https://doi.org/10.1111/j.1399-0004.2006.00559.x]
Fry, A. C., Karet, F. E. Inherited renal acidoses. Physiology 22: 202-211, 2007. [PubMed: 17557941] [Full Text: https://doi.org/10.1152/physiol.00044.2006]
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]
Konigsmark, B. W. Personal Communication. Baltimore, Md. 1966.
Nance, W. E., Sweeney, A., McLeod, A. C., Cooper, M. C. Hereditary deafness: a presentation of some recognized types, modes of inheritance, and aids in counseling. Sth. Med. Bull. 58: 41-57, 1970.
Nance, W. E., Sweeney, A. Evidence for autosomal recessive inheritance of the syndrome of renal tubular acidosis with deafness. Birth Defects Orig. Art. Ser. VII(4): 70-72, 1971.
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]
Shapira, E., Ben-Yoseph, Y., Eyal, G., Russell, A. Enzymatically inactive red cell carbonic anhydrase B in a family with renal tubular acidosis. J. Clin. Invest. 53: 59-63, 1974. [PubMed: 4202671] [Full Text: https://doi.org/10.1172/JCI107559]
Simon, H., Orive, B., Zamora, I., Mendizabal, S. The acidification defect in the syndrome of renal tubular acidosis with nerve deafness. Acta Paediat. Scand. 68: 291-295, 1979. [PubMed: 419999] [Full Text: https://doi.org/10.1111/j.1651-2227.1979.tb05007.x]
Sly, W. S. The carbonic anhydrase II deficiency syndrome: osteopetrosis with renal tubular acidosis and cerebral calcification.In: Scriver, C. R.; Beaudet, A. L.; Sly, W. S.; Valle, D. (eds.) : The Metabolic Basis of Inherited Disease. (6th ed.) New York: McGraw-Hill (pub.) 1989.
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]
Tashian, R. E., Kendall, A. G., Carter, N. D. Inherited variants of human red cell carbonic anhydrase. Hemoglobin 4: 635-651, 1980. [PubMed: 6777336] [Full Text: https://doi.org/10.3109/03630268008997733]
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]
Walker, W. G. Renal tubular acidosis and deafness. Birth Defects Orig. Art. Ser. VII(4): 126 only, 1971.