Mutations in ATP6V1B1 and ATP6V0A4 genes cause recessive distal renal tubular acidosis in Mexican families

Abstract

BackgroundAutosomal recessive distal renal tubular acidosis (dRTA) is a rare disease characterized by a hyperchloremic metabolic acidosis with normal anion gap, hypokalemia, hypercalciuria, hypocitraturia, nephrocalcinosis, and conserved glomerular filtration rate. In some cases, neurosensorial deafness is associated. dRTA is developed during the first months of life and the main manifestations are failure to thrive, vomiting, dehydration, and anorexia.MethodsNine unrelated families were studied: seven children, a teenager, and an adult with dRTA. Hearing was preserved in four children. Coding regions of the genes responsible for recessive dRTA were analysed by Sanger sequencing.ResultsMolecular defects were found in the genes ATP6V1B1 and ATP6V0A4. We identified three homozygous variants in ATP6V1B: a frameshift mutation (p.Ile386Hisfs*56), a nucleotide substitution in exon 10 (p.Pro346Arg), and a new splicing mutation in intron 5. Three patients were homozygous for one novel (p.Arg743Trp) and one known (p.Asp411Tyr) missense mutations in the ATP6V0A4 gene. Three patients were compound heterozygous: one proband displayed two novel mutations, the frameshift mutation p.Val52Metfs*25, and a large deletion of exons 18–21; two probands showed the missense mutation p.Asp411Tyr and as a second mutation, p.Arg194Ter and c.1691+2dup, respectively.Conclusion ATP6V0A4 and ATP6V1B1 genes were involved in recessive dRTA of Mexican families. All ATP6V1B1 mutations detected were homozygous and all patients developed sensorineural hearing loss (SNHL) early in infancy. ATP6V0A4 mutations were found in one infant and three children without SNHL, and in one teenager and one adult with SNHL confirming the phenotypic variability in this trait. The mutation p.Asp411Tyr detected in four Mexican families was due to a founder effect. Screening of these mutations could provide a rapid and valuable tool for diagnosis of dRTA in this population.

Nephrolithiasis secondary to inherited defects in the thick ascending loop of henle and connecting tubules

“…B1 and a4 subunits of the V-ATPase are expressed in the stria vascularis of the inner ear and almost all patients with recessive ATP6V1B1 mutations and about half of patients with recessive ATP6V0A4 mutations develop progressive, bilateral sensorineural hearing loss [104]. For unknown reasons, onset of hearing loss occurs at a younger age and the phenotype is more severe in patients with ATP6V1B1 mutations [105,109,104]. Sensorineural hearing loss can be accompanied by enlargement of the vestibular aqueduct and endolymphatic sac and may contribute to the onset or the progression of hearing impairment [110][111][112].…”

A subunit of V-ATPases, ATP6V1B2, underlies the pathology of intellectual disability

“…As proton pumps are present in the membranes of intracellular organelles, such as dictyosomes, endosomes, lysosomes, and synaptic vesicles, wherein acidification is vital, V-ATPases are very important for the development of multicellular life [5], and for multiple cellular functions including vesicular trafficking, lysosome degradation, and acidification of intracellular organelles [4,6,7]. Accordingly, V-ATPases has been implicated in a number of diseases, including neurodegeneration [8], cutis laxa [9], bone disease [10], cancer [11], renal disease, and deafness [12]. There exist two highly homologous isoforms of the B subunit (56 kDa) of V-ATPases in mammals: B1 (encoded by ATP6V1B1 ) and B2.…”

“…ATP6V1B1 is associated with distal renal tubular acidosis (dRTA, MIM: 602722), a rare disease characterized by metabolic acidosis and sensorineural deafness [12], while ATP6V1B2 is the disease-causing gene of dominant deafness-onychodystrophy syndrome (DDOD syndrome, MIM: 124480) and Zimmermann-Laband syndrome (ZLS, MIM: 135500). DDOD syndrome, which forms the backdrop of the current study, is an autosomal dominant genetic disease that leads to severe congenital sensorineural deafness, absence of nails and/or toes, the presence of pointed teeth in some cases, onychodystrophy, and brachydactyly.…”

Distal renal tubular acidosis. Clinical manifestations in patients with different underlying gene mutations

“…As expected, none of patients harboring SLC4A1 gene defects had deafness because the Cl − /HCO3 − anion exchanger does not express in the ears. It was classically assumed that dRTA caused by defective ATP6V1B1 gene was associated with early nerve hearing loss [7,28,[30][31][32][33], while ATP6V0A4 mutations were related with either late-onset deafness or normal hearing, [34][35][36][37][38][39][40]. Vargas-Poussou et al [41] challenged this assumption demonstrating genetic heterogeneity in dRTA associated with deafness and emphasizing the importance of mutational gene analysis for recessive forms of dRTA independent of Fig.…”