OXGR1 is a candidate disease gene for human calcium oxalate nephrolithiasis

Amar J Majmundar; Eugen Widmeier; John F Heneghan; Ankana Daga; Chen-Han Wilfred Wu; Florian Buerger; Hannah Hugo; Ihsan Ullah; Ali Amar; Isabel Ottlewski; Daniela A Braun; Tilman Jobst-Schwan; Jennifer A Lawson; Muhammad Yasir Zahoor; Nancy M Rodig; Velibor Tasic; Caleb P Nelson; Shagufta Khaliq; Ria Schönauer; Jan Halbritter; John A Sayer; Hanan M Fathy; Michelle A Baum; Shirlee Shril; Shrikant Mane; Seth L Alper; Friedhelm Hildebrandt

doi:10.1016/j.gim.2022.11.019

OXGR1 is a candidate disease gene for human calcium oxalate nephrolithiasis

Genet Med. 2023 Mar;25(3):100351. doi: 10.1016/j.gim.2022.11.019. Epub 2022 Dec 6.

Authors

Amar J Majmundar¹, Eugen Widmeier¹, John F Heneghan², Ankana Daga¹, Chen-Han Wilfred Wu³, Florian Buerger¹, Hannah Hugo¹, Ihsan Ullah⁴, Ali Amar⁵, Isabel Ottlewski¹, Daniela A Braun¹, Tilman Jobst-Schwan⁶, Jennifer A Lawson¹, Muhammad Yasir Zahoor⁴, Nancy M Rodig¹, Velibor Tasic⁷, Caleb P Nelson⁸, Shagufta Khaliq⁹, Ria Schönauer¹⁰, Jan Halbritter¹⁰, John A Sayer¹¹, Hanan M Fathy¹², Michelle A Baum¹, Shirlee Shril¹, Shrikant Mane¹³, Seth L Alper², Friedhelm Hildebrandt¹⁴

Affiliations

¹ Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA.
² Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA.
³ Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA; Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA; Departments of Urology and Genetics and Genome Sciences, School of Medicine, Case Western Reserve University and University Hospitals, Cleveland, OH.
⁴ Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA; Molecular Biology Laboratory, Institute of Biochemistry and Biotechnology, University of Veterinary & Animal Sciences, Lahore, Pakistan.
⁵ Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA; Department of Human Genetics and Molecular Biology, University of Health Sciences Lahore, Lahore, Pakistan.
⁶ Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA; Department of Nephrology and Hypertension, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
⁷ Medical Faculty Skopje, University Children's Hospital, Skopje, North Macedonia.
⁸ Department of Urology, Boston Children's Hospital and Department of Surgery, Harvard Medical School, Boston, MA.
⁹ Department of Human Genetics and Molecular Biology, University of Health Sciences Lahore, Lahore, Pakistan.
¹⁰ Division of Nephrology, Department of Internal Medicine, University of Leipzig, Leipzig, Germany; Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Berlin, Germany.
¹¹ Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom; The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, United Kingdom; NIHR Newcastle Biomedical Research Centre, Newcastle, United Kingdom.
¹² Pediatric Nephrology Unit, Alexandria University, Alexandria, Egypt.
¹³ Department of Genetics and Yale Center for Mendelian Genomics, Yale University School of Medicine, New Haven, CT.
¹⁴ Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA. Electronic address: [email protected].

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: Alpha-ketoglutarate; Calcium oxalate; Genetics; Nephrolithiasis.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Calcium Oxalate
Humans
Mutation, Missense / genetics
Nephrolithiasis* / genetics
Receptors, Purinergic P2* / genetics
Receptors, Purinergic P2* / metabolism
Sulfate Transporters / genetics

OXGR1 is a candidate disease gene for human calcium oxalate nephrolithiasis

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