Whole exome sequencing identified ATP6V1C2 as a novel candidate gene for recessive distal renal tubular acidosis.

Abstract

Distal renal tubular acidosis is a rare renal tubular disorder characterized by hyperchloremic metabolic acidosis and impaired urinary acidification. Mutations in three genes (ATP6V0A4, ATP6V1B1 and SLC4A1) constitute a monogenic causation in 58-70% of familial cases of distal renal tubular acidosis. Recently, mutations in FOXI1 have been identified as an additional cause. Therefore, we hypothesized that further monogenic causes of distal renal tubular acidosis remain to be discovered. Panel sequencing and/or whole exome sequencing was performed in a cohort of 17 families with 19 affected individuals with pediatric onset distal renal tubular acidosis. A causative mutation was detected in one of the three "classical" known distal renal tubular acidosis genes in 10 of 17 families. The seven unsolved families were then subjected to candidate whole exome sequencing analysis. Potential disease causing mutations in three genes were detected: ATP6V1C2, which encodes another kidney specific subunit of the V-type proton ATPase (1 family); WDR72 (2 families), previously implicated in V-ATPase trafficking in cells; and SLC4A2 (1 family), a paralog of the known distal renal tubular acidosis gene SLC4A1. Two of these mutations were assessed for deleteriousness through functional studies. Yeast growth assays for ATP6V1C2 revealed loss-of-function for the patient mutation, strongly supporting ATP6V1C2 as a novel distal renal tubular acidosis gene. Thus, we provided a molecular diagnosis in a known distal renal tubular acidosis gene in 10 of 17 families (59%) with this disease, identified mutations in ATP6V1C2 as a novel human candidate gene, and provided further evidence for phenotypic expansion in WDR72 mutations from amelogenesis imperfecta to distal renal tubular acidosis.

• Authors: Tilman Jobst-Schwan, Verena Klämbt, Maureen Tarsio, John F Heneghan, Amar J Majmundar, Shirlee Shril, Florian Buerger, Isabel Ottlewski, Boris E Shmukler, Rezan Topaloglu, Seema Hashmi, Farkhanda Hafeez, Francesco Emma, Marcella Greco, Guido F Laube, Hanan M Fathy, Martin Pohl, Jutta Gellermann, Danko Milosevic, Michelle A Baum, Shrikant Mane, Richard P Lifton, Patricia M Kane, Seth L Alper, Friedhelm Hildebrandt
• Journal: Kidney international (Kidney Int) Vol. 97 Issue 3 Pg. 567-579 (03 2020) ISSN: 1523-1755 [Electronic] United States
• PMID: 31959358 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2019 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.

Chemical References

• ATP6V1B1 protein, human
• Anion Exchange Protein 1, Erythrocyte
• Chloride-Bicarbonate Antiporters
• FOXI1 protein, human
• Forkhead Transcription Factors
• SLC4A1 protein, human
• SLC4A2 protein, human
• Vacuolar Proton-Translocating ATPases

Topics

• Acidosis, Renal Tubular (genetics)
• Anion Exchange Protein 1, Erythrocyte
• Child
• Chloride-Bicarbonate Antiporters
• DNA Mutational Analysis
• Forkhead Transcription Factors
• Humans
• Mutation
• Vacuolar Proton-Translocating ATPases (genetics)
• Exome Sequencing