ABSTRACT
Purpose
Nephrolithiasis (NL) affects 1 in 11 individuals worldwide, leading to significant
patient morbidity. NL is associated with nephrocalcinosis (NC), a risk factor for
chronic kidney disease. Causative genetic variants are detected in 11% to 28% of NL
and/or NC, suggesting that additional NL/NC-associated genetic loci await discovery.
Therefore, we employed genomic approaches to discover novel genetic forms of NL/NC.
Methods
Exome sequencing and directed sequencing of the OXGR1 locus were performed in a worldwide NL/NC cohort. Putatively deleterious, rare OXGR1 variants were functionally characterized.
Results
Exome sequencing revealed a heterozygous OXGR1 missense variant (c.371T>G, p.L124R) cosegregating with calcium oxalate NL and/or
NC disease in an autosomal dominant inheritance pattern within a multigenerational
family with 5 affected individuals. OXGR1 encodes 2-oxoglutarate (α-ketoglutarate [AKG]) receptor 1 in the distal nephron.
In response to its ligand AKG, OXGR1 stimulates the chloride-bicarbonate exchanger,
pendrin, which also regulates transepithelial calcium transport in cortical connecting
tubules. Strong amino acid conservation in orthologs and paralogs, severe in silico
prediction scores, and extreme rarity in exome population databases suggested that
the variant was deleterious. Interrogation of the OXGR1 locus in 1107 additional NL/NC families identified 5 additional deleterious dominant
variants in 5 families with calcium oxalate NL/NC. Rare, potentially deleterious OXGR1 variants were enriched in patients with NL/NC compared with Exome Aggregation Consortium
controls (χ2 = 7.117, P = .0076). Wild-type OXGR1-expressing Xenopus oocytes exhibited AKG-responsive Ca2+ uptake. Of 5 NL/NC-associated missense variants, 5 revealed impaired AKG-dependent
Ca2+ uptake, demonstrating loss of function.
Conclusion
Rare, dominant loss-of-function OXGR1 variants are associated with recurrent calcium oxalate NL/NC disease.
Keywords
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Article info
Publication history
Published online: November 29, 2022
Accepted:
November 27,
2022
Received in revised form:
November 23,
2022
Received:
August 8,
2022
Footnotes
Amar J. Majmundar, Eugen Widmeier, and John F. Heneghan contributed equally.
Identification
Copyright
© 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.
