OXGR1 is a candidate disease gene for human calcium oxalate nephrolithiasis.

Autor:	Majmundar AJ; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA., Widmeier E; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA., Heneghan JF; Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA., Daga A; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA., Wu CW; 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., Buerger F; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA., Hugo H; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA., Ullah I; 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., Amar A; 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., Ottlewski I; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA., Braun DA; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA., Jobst-Schwan T; 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., Lawson JA; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA., Zahoor MY; 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., Rodig NM; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA., Tasic V; Medical Faculty Skopje, University Children's Hospital, Skopje, North Macedonia., Nelson CP; Department of Urology, Boston Children's Hospital and Department of Surgery, Harvard Medical School, Boston, MA., Khaliq S; Department of Human Genetics and Molecular Biology, University of Health Sciences Lahore, Lahore, Pakistan., Schönauer R; Division of Nephrology, Department of Internal Medicine, University of Leipzig, Leipzig, Germany; Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Berlin, Germany., Halbritter J; Division of Nephrology, Department of Internal Medicine, University of Leipzig, Leipzig, Germany; Department of Nephrology and Medical Intensive Care, Charité - Universitätsmedizin Berlin, Berlin, Germany., Sayer JA; 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., Fathy HM; Pediatric Nephrology Unit, Alexandria University, Alexandria, Egypt., Baum MA; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA., Shril S; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA., Mane S; Department of Genetics and Yale Center for Mendelian Genomics, Yale University School of Medicine, New Haven, CT., Alper SL; Division of Nephrology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA., Hildebrandt F; Division of Nephrology, Department of Pediatrics, Boston Children's Hospital, Harvard Medical School, Boston, MA. Electronic address: friedhelm.hildebrandt@childrens.harvard.edu.
Jazyk:	angličtina
Zdroj:	Genetics in medicine : official journal of the American College of Medical Genetics [Genet Med] 2023 Mar; Vol. 25 (3), pp. 100351. Date of Electronic Publication: 2022 Dec 06.
DOI:	10.1016/j.gim.2022.11.019
Abstrakt:	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 (χ 2  = 7.117, P = .0076). Wild-type OXGR1-expressing Xenopus oocytes exhibited AKG-responsive Ca 2+ uptake. Of 5 NL/NC-associated missense variants, 5 revealed impaired AKG-dependent Ca 2+ uptake, demonstrating loss of function. Conclusion: Rare, dominant loss-of-function OXGR1 variants are associated with recurrent calcium oxalate NL/NC disease. Competing Interests: Conflict of Interest F.H. is a cofounder of Goldfinch Bio, Inc. S.L.A. is a consultant to and received funding from Quest Diagnostics, Inc. All other authors declare no conflicts of interest. (Copyright © 2022 American College of Medical Genetics and Genomics. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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