Abstract

A rare renal tubular disorder called distal renal tubular acidosis is characterized by impaired urinary acidification and hyperchloremic metabolic acidosis. 58-70% of familial cases of distal renal tubular acidosis are caused by mutations in three genes: ATP6V0A4, ATP6V1B1, and SLC4A1. An additional cause has recently been identified as FOXI1 mutations. As a result, we speculated that additional monogenic causes of distal renal tubular acidosis remain unknown.A group of 17 families and 19 affected individuals with pediatric-onset distal renal tubular acidosis underwent panel or whole exome sequencing. In 10 of the 17 families, a mutation in one of the three “classical” genes associated with distal renal tubular acidosis was found to be the cause. After that, candidate whole exome sequencing analysis was performed on the seven unsolved families. Three genes showed potential mutations that could cause a disease:Another kidney-specific subunit of the V-type proton ATPase (one family) is encoded by ATP6V1C2. WDR72 (two families), previously thought to be involved in cell V-ATPase trafficking; and SLC4A2, a member of the same family as the known gene for distal renal tubular acidosis, SLC4A1. Functional studies were used to determine the negative effects of two of these mutations. The patient’s loss-of-function mutation in yeast growth assays for ATP6V1C2 strongly suggests that it is a novel gene for distal renal tubular acidosis. As a result, we identified mutations in ATP6V1C2 as a novel human candidate gene, provided additional evidence for phenotypic expansion of WDR72 mutations from amelogenesis imperfecta to distal renal tubular acidosis, and provided a molecular diagnosis in a known distal renal tubular acidosis gene in 10 of 17 families (59 percent) with this disease.