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Abstract: TH-PO816

Whole-Exome Sequencing Reveals ATP6V1C2 as a Novel Candidate Gene for Recessive Distal Renal Tubular Acidosis

Session Information

Category: Genetic Diseases of the Kidneys

  • 1002 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Jobst-Schwan, Tilman, Boston Children's Hospital, Boston, Massachusetts, United States
  • Klambt, Verena, Boston Children's Hospital, Boston, Massachusetts, United States
  • Majmundar, Amar J., Boston Children's Hospital, Boston, Massachusetts, United States
  • Shril, Shirlee, Boston Children's Hospital, Boston, Massachusetts, United States
  • Buerger, Florian, Boston Children's Hospital, Boston, Massachusetts, United States
  • Ottlewski, Isabel, Boston Children's Hospital, Boston, Massachusetts, United States
  • Topaloglu, Rezan, Hacettepe University, Ankara, Turkey
  • Milosevic, Danko, Zagreb School of Medicine, Clinical Hospital Centre Zagreb, Zagreb, Croatia
  • Baum, Michelle Amy, Boston Children's Hospital, Boston, Massachusetts, United States
  • Kane, Patricia M., SUNY Upstate Medical University, Syracuse, New York, United States
  • Alper, Seth L., Beth Israel Deaconess Medical Center, Boston, Massachusetts, United States
  • Hildebrandt, Friedhelm, Boston Children's Hospital, Boston, Massachusetts, United States
Background

Distal renal tubular acidosis (dRTA) is a rare renal tubular disorder characterized by hyperchloremic metabolic acidosis and impaired urinary acidification. Mutations in 3 genes (ATP6V0A4, ATP6V1B1 and SLC4A1) constitute a monogenic causation in 58-70% of familial childhood-onset dRTA cases. ATP6V0A4 and ATP6V1B1 both encode for subunits of the vacuolar V-ATPase.
Just recently, mutations in FOXI1 have been identified as an additional cause. Therefore, we hypothesized that additional monogenic causes of dRTA remain to be discovered.

Methods

We performed panel sequencing and whole exome sequencing (WES) in a cohort of 17 families with 19 affected individuals with pediatric onset dRTA. Yeast growth assays and immunoblot analysis of vacuolar V-ATPase subunits were performed for ATP6V1C2. Transmembranous transport experiments were performed for SLC4A2 after expression in Xenopus oocytes.

Results

We identified a causative mutation in 1 of the 3 “classical” known dRTA genes in 10/17 families (58%). Genomic DNA of the 7 unsolved families was then subjected to WES analysis. We identified mutations in 3 genes: ATP6V1C2, which encodes another kidney- specific subunit of the V-type proton ATPase (1 family); WDR72 (2 families) which is an established disease gene for amelogenesis imperfecta, but was also previously implicated in V-ATPase trafficking in cells; and SLC4A2 (1 family), a paralog of known dRTA gene SLC4A1. We then assessed 2 of these mutations for deleteriousness through functional studies. Yeast growth assays and immunoblot analysis of vacuolar V-ATPase subunits for ATP6V1C2 revealed loss-of-function for the patient mutation with impairment of V-ATPase stability, strongly supporting ATP6V1C2 as a novel dRTA gene. In contrast, Xenopus oocyte experiments did not reveal a functional impact of the SLC4A2 mutation in the transmembranous transport experiments.

Conclusion

We provided a molecular diagnosis in a known dRTA gene in 10/17 families with dRTA (58%), identified a mutation in ATP6V1C2 as a novel human dRTA candidate gene, and provided further evidence for phenotypic expansion in WDR72 mutations from amelogenesis imperfecta to dRTA.

Funding

  • NIDDK Support