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.
Highlights
ATP6V0A4 mutations were found in one infant and three children without sensorineural hearing loss (SNHL), and in one teenager and one adult with SNHL confirming the phenotypic variability in this trait
Hereditary distal renal tubular acidosis results from mutations in genes encoding for three proteins expressed in a-intercalated cells of the collecting duct: the a4 and B1 subunits of the V-ATPase and the anion exchanger ClÀ/HCO3À
Clinical diagnosis was supported by the presence of hyperchloremic metabolic acidosis with normal anion gap, hypercalciuria, hypokalemia, nephrocalcinosis, polyuria, and failure to thrive
Summary
Hereditary distal renal tubular acidosis (dRTA) results from mutations in genes encoding for three proteins expressed in a-intercalated cells of the collecting duct: the a4 and B1 subunits of the V-ATPase and the anion exchanger ClÀ/HCO3À (kAE1). The V-ATPase is expressed in the acid secretory a-intercalated cells of the cortical and medullary collecting duct in the kidney and in the epithelial cells of the endolymphatic sac in the cochlea (Dou et al 2004). Mutations in these genes impair the V-ATPase proton-secreting function and produce the autosomal recessive form of dRTA, which can be associated with sensorineural hearing loss (SNHL) (Smith et al 2000; Stover et al 2002; Vargas-Poussou et al 2006). 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
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