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

Jobst-Schwan T, Klambt V, Tarsio M, Heneghan JF, Majmundar AJ, Shril S, Buerger F, Ottlewski I, Shmukler BE, Topaloglu R, Hashmi S, Hafeez F, Emma F, Greco M, Laube GF, Fathy HM, Pohl M, Gellermann J, Milosevic D, Baum MA, Mane S, Lifton RP, Kane PM, Alper SL, Hildebrandt F (2020)

Publication Type: Journal article

Publication year: 2020

Journal

Kidney International Nature Publishing Group: Open Access Hybrid Model Option A

Book Volume: 97

Pages Range: 567-579

Journal Issue: 3

DOI: 10.1016/j.kint.2019.09.026

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 with CRIS profile

Tilman Jobst-Schwan

Involved external institutions

Harvard University US United States (USA) (US) Alexandria University / جامعة الإسكندرية‎‎ EG Egypt (EG) State University of New York at Albany (UNY Albany / UAlbany) US United States (USA) (US) University of Zagreb / Sveučilište u Zagrebu HR Croatia (HR) Albert-Ludwigs-Universität Freiburg DE Germany (DE) Ospedale Pediatrico Bambino Gesu IT Italy (IT) Children Hospital Lahore PK Pakistan (PK) Yale University US United States (USA) (US) Hacettepe University TR Turkey (TR) Sindh Institute of Urology and Transplantation PK Pakistan (PK) Charité - Universitätsmedizin Berlin DE Germany (DE) Universitäts-Kinderspital Zürich CH Switzerland (CH)

How to cite

APA:

Jobst-Schwan, T., Klambt, V., Tarsio, M., Heneghan, J.F., Majmundar, A.J., Shril, S.,... Hildebrandt, F. (2020). Whole exome sequencing identified ATP6V1C2 as a novel candidate gene for recessive distal renal tubular acidosis. Kidney International, 97(3), 567-579. https://doi.org/10.1016/j.kint.2019.09.026

MLA:

Jobst-Schwan, Tilman, et al. "Whole exome sequencing identified ATP6V1C2 as a novel candidate gene for recessive distal renal tubular acidosis." Kidney International 97.3 (2020): 567-579.

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