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Abstract: SA-PO566

OXGR1 Is a Candidate Disease Gene for Human Calcium Oxalate Nephrolithiasis

Session Information

  • Genetic Diseases: Diagnosis
    November 05, 2022 | Location: Exhibit Hall, Orange County Convention Center‚ West Building
    Abstract Time: 10:00 AM - 12:00 PM

Category: Genetic Diseases of the Kidneys

  • 1102 Genetic Diseases of the Kidneys: Non-Cystic

Authors

  • Majmundar, Amar J., Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Widmeier, Eugen, Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Heneghan, John F., Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States
  • Daga, Ankana, Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Hugo, Hannah, Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Amar, Ali, Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, United States
  • Jobst-Schwan, Tilman, Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, United States
  • Nelson, Caleb, Department of Urology, Boston Children’s Hospital and Department of Surgery, Harvard Medical School, Boston, Massachusetts, United States
  • Halbritter, Jan, Division of Nephrology, Department of Internal Medicine, University of Leipzig, Leipzig, Germany
  • Sayer, John Andrew, Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom
  • Fathy, Hanan, Pediatric Nephrology Unit, Alexandria University, Alexandria, Egypt
  • Baum, Michelle Amy, Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Shril, Shirlee, Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States
  • Mane, Shrikant M., Department of Genetics, Yale University School of Medicine, New Haven, Connecticut, United States
  • Alper, Seth L., Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, United States
  • Hildebrandt, Friedhelm, Division of Nephrology, Department of Medicine, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, United States
Background

Nephrolithiasis (NL) affects 1 in 11 individuals worldwide. Causative genetic variants are detected in 11-28% of NL and/or associated nephrocalcinosis (NC) (Halbritter JASN 2015; Braun cJASN 2016; Daga KI 2018). OXGR1 encodes 2-oxoglutarate receptor 1, which is expressed in collecting duct Type B intercalated cells. OXGR1 mediates cellular Ca2+ uptake in response to α-ketoglutarate (AKG) (He Nature 2004), a renally excreted metabolite derived from the NL treatment citrate (Krebs Biochem J 1938; Coe Nat Rev Neph 2016). Genetic inactivation in mice of the Oxgr1 effector Pendrin leads to hypercalciuria, a risk factor for NL/NC (Tokonami JCI 2013; Amlal AJPCP 2010; Barone NDT 2016).

Methods

Exome and targeted sequencing of the OXGR1 locus was performed in a worldwide NL/NC cohort. Putatively deleterious rare OXGR1 variants were functionally characterized.

Results

A heterozygous missense OXGR1 variant (c.371T>G, p.L124R) co-segregated with calcium oxalate NL/NC in an autosomal dominant inheritance pattern within a multi-generational family with five affected individuals. Strong amino acid conservation in orthologues and paralogues, severe in silico prediction scores (SIFT, PolyPhen2.0, CADD), and extreme rarity in exome/genome population databases suggested the variant was deleterious. Interrogation of the OXGR1 locus in 1107 NL/NC families identified five additional dominant alleles (p.Ser56Profs*7, p.Tyr93His, p.Cys217Arg, p.Ser233Arg, p.Ser287Phe) in five families with calcium oxalate NL/NC. All were rare variants (<5 alleles in ExAC, <10 alleles in gnomAD) with multiple severe prediction scores. Rare, potentially deleterious OXGR1 variants were enriched in NL/NC subjects relative to ExAC controls (0.54% versus 0.16%; Χ2=7.117, p=0.0076). Wildtype OXGR1-expressing Xenopus oocytes exhibited AKG-responsive Ca2+ uptake. Four of five NL/NC-associated missense variants revealed impaired AKG-dependent Ca2+ uptake at pH 5 and/or 7.4, demonstrating loss-of-function.

Conclusion

Rare, dominant OXGR1 variants are a candidate etiology of NL/NC, suggesting a novel mechanism for human NL/NC disease.

Funding

  • NIDDK Support