Novel ATP6V1B1 and ATP6V0A4 mutations in autosomal recessive distal renal tubular acidosis with new evidence for hearing loss

Abstract

Autosomal recessive distal renal tubular acidosis (rdRTA) is characterised by severe hyperchloraemic metabolic acidosis in childhood, hypokalaemia, decreased urinary calcium solubility, and impaired bone physiology and growth. Two types of rdRTA have been differentiated by the presence or absence of sensorineural hearing loss, but appear otherwise clinically similar. Recently, we identified mutations in genes encoding two different subunits of the renal α-intercalated cell's apical H + -ATPase that cause rdRTA. Defects in the B1 subunit gene ATP6V1B1, and the a4 subunit gene ATP6V0A4, cause rdRTA with deafness and with preserved hearing, respectively. We have investigated 26 new rdRTA kindreds, of which 23 are consanguineous. Linkage analysis of seven novel SNPs and five polymorphic markers in, and tightly linked to, ATP6V1B1 and ATP6V0A4 suggested that four families do not link to either locus, providing strong evidence for additional genetic heterogeneity. In ATP6V1B1, one novel and five previously reported mutations were found in 10 kindreds. In 12 ATP6V0A4 kindreds, seven of 10 mutations were novel. A further nine novel ATP6V0A4 mutations were found in "sporadic" cases. The previously reported association between ATP6V1B1 defects and severe hearing loss in childhood was maintained. However, several patients with ATP6V0A4 mutations have developed hearing loss, usually in young adulthood. We show here that ATP6V0A4 is expressed within the human inner ear. These findings provide further evidence for genetic heterogeneity in rdRTA, extend the spectrum of disease causing mutations in ATP6V1B1 and ATP6V0A4, and show ATP6V0A4 expression within the cochlea for the first time.A cid-base regulation by the kidney is tightly controlled through the coupled processes of acid secretion and bicarbonate reabsorption via intercalated cells of the nephron's collecting duct segment. The result is regulated secretion into the urine of the net acid load provided by the human diet. The main proton pump responsible for urinary acidification by α-intercalated cells, the apical H + -ATPase, is a multi-subunit structure with a "head and stalk" configuration. The V 1 (head) and V 0 (membrane anchored) domains are responsible for ATP hydrolysis and transmembrane proton translocation respectively.

A 600 kb triplication in the cat eye syndrome critical region causes anorectal, renal and preauricular anomalies in a three-generation family

“…Mutations in other subunits of the V-ATPase complex have shown to be involved in distal renal tubular acidosis and sensorineural deafness. 20 In conclusion, CECR2, SLC25A18 and ATP6V1E1 are strong candidate genes in causing anal atresia, preauricular pits or tags and kidney anomalies in the described family members and consequently in causing these frequent components of the CES phenotype spectrum.…”

Genetic Investigation of Autosomal Recessive Distal Renal Tubular Acidosis

“…These families did not all have the same haplotype at the ATP6V1B1 locus. This I386fsX441 mutation was previously described in six families from Saudi Arabia, Sicily, Morocco, Sweden, and Spain (4,6). A novel mutation in intron 2, affecting the splice acceptor site (IVS2-1GϾC), was identified in three probands.…”

“…The spectrum of severity of SNHL and the range of ages over which hearing loss occurs in patients with ATP6V0A4 mutations are unclear. Finally, there is evidence that the recessive forms are genetically more heterogeneous (6).…”

“…The autosomal dominant form (OMIM 179800) is caused by mutations in the gene encoding the basolateral Cl Ϫ /HCO 3 Ϫ exchanger (SLC4A) (3). Autosomal recessive forms have been associated with mutations in the B1 subunit of the apical H ϩ ATPase gene (ATP6V1B1, initially known as ATP6B1) in individuals who display sensorineural hearing loss (SNHL; OMIM 267300) (4) or with mutations in the a4 subunit of the apical H ϩ ATPase gene (ATP6V0A4, initially known as ATP6N1B or ATP6N2) in individuals who do not have SNHL or display hearing loss only after the age of 10 yr (OMIM 602722) (5,6). However, at least two cases of ATP6V1B1 mutation without SNHL have been described (4,7).…”

Audiological Correlates of Renal Tubular Acidosis - A Case Report

“…Primary distal renal tubular acidosis (dRTA) [1] is characterized by hyperchloremic metabolic acidosis due to failure in proton excretion, variably severe nephrocalcinosis and/or nephrolithiasis associated with hypercalciuria and hypocitraturia. Mutations of ATP6V1B1 or ATPV0A4 genes, causes sensorineural hearing loss in renal tubular acidosis [2]. The former is associated with early onset of hearing loss and the latter with late onset.…”