OXGR1 is a candidate disease gene for human calcium oxalate nephrolithiasis |
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| Affiliation: | 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 Genetics and Genomics, Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School, Boston, MA;4. Departments of Urology and Genetics and Genome Sciences, School of Medicine, Case Western Reserve University and University Hospitals, Cleveland, OH;5. Molecular Biology Laboratory, Institute of Biochemistry and Biotechnology, University of Veterinary & Animal Sciences, Lahore, Pakistan;6. Department of Human Genetics and Molecular Biology, University of Health Sciences Lahore, Lahore, Pakistan;7. Department of Nephrology and Hypertension, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany;8. Medical Faculty Skopje, University Children’s Hospital, Skopje, North Macedonia;9. Department of Urology, Boston Children’s Hospital and Department of Surgery, Harvard Medical School, Boston, MA;10. Division of Nephrology, Department of Internal Medicine, University of Leipzig, Leipzig, Germany;11. Department of Nephrology and Medical Intensive Care, Charité ? Universitätsmedizin Berlin, Berlin, Germany;12. Institute of Genetic Medicine, Newcastle University, Newcastle, United Kingdom;13. The Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle, United Kingdom;14. NIHR Newcastle Biomedical Research Centre, Newcastle, United Kingdom;15. Pediatric Nephrology Unit, Alexandria University, Alexandria, Egypt;16. Department of Genetics and Yale Center for Mendelian Genomics, Yale University School of Medicine, New Haven, CT;1. The South African MRC/UCT Genomic and Precision Medicine Research Unit, Division of Human Genetics, Institute of Infectious Diseases and Molecular Medicine, Department of Pathology, Faculty of Health Sciences, University of Cape Town, Cape Town, South Africa;2. National Health Laboratory Service, Groote Schuur Hospital, Cape Town, South Africa;3. South African National Bioinformatics Institute, University of the Western Cape, Bellville, Western Cape, South Africa;4. Department of Paediatric Neurology, Red Cross War Memorial Children’s Hospital, Neuroscience Institute, University of Cape Town, Cape Town, South Africa;5. Division of Clinical Neurology, Nuffield Department of Clinical Neurosciences, John Radcliffe Hospital, University of Oxford, Oxford, United Kingdom;6. Ken and Ruth Davee Department of Neurology, Northwestern University Feinberg School of Medicine, Northwestern University, Chicago, IL;7. Department of Pediatrics, University of Washington, Seattle, WA;8. Department of Genome Sciences, University of Washington, Seattle, WA;9. Brotman Baty Institute, Seattle, WA;10. Centre for Pediatric Neurological Disease Research, St. Jude Children’s Research Hospital, Memphis, TN;11. Department of Pharmacology, Northwestern University Feinberg School of Medicine, Northwestern University, Chicago, IL;12. Department of Pediatrics, Northwestern University Feinberg School of Medicine, Northwestern University, Chicago, IL;1. Division of Medical Genetics, Department of Pediatrics, Duke University School of Medicine, Durham, NC;2. Stanford Center for Inherited Cardiovascular Disease, Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA;3. Stanford Center for Undiagnosed Diseases, Stanford University, and Department of Pediatrics, Stanford University School of Medicine, Stanford, CA;4. Institute for Genome Medicine, Columbia University Medical Center, New York, NY;1. Graduate School of Health, University of Technology Sydney, Ultimo, New South Wales, Australia;2. Stanford Center for Undiagnosed Diseases, Standard University, Stanford, CA;3. Department of Medical Social Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL;4. Rare Disease Institute, Children''s National Hospital, Washington, DC;5. National Human Genome Research Institute, National Institutes of Health, Bethesda, MD;6. Center for Health Research, Kaiser Permanente Northwest, Portland, OR;7. Treuman Katz Center for Pediatric Bioethics, Seattle Children’s Hospital, Seattle, WA;8. Genomics, Ethics, and Translational Research Program, RTI International, Washington, DC;1. Departamento de Enfermería, Facultad de Medicina, Universidad Autónoma de Madrid, Madrid, España;2. Servicio de Cuidados Intensivos, Hospital Universitario de Getafe, Getafe, Madrid, España;1. Functional Unit for Diagnostic Innovation in Rare Diseases, FHU-TRANSLAD, Dijon Bourgogne University Hospital, Dijon, France;2. INSERM UMR1231 GAD “Génétique des Anomalies du Développement,” FHU-TRANSLAD, University of Burgundy, Dijon, France;3. CNAG-CRG, Centre for Genomic Regulation,” The Barcelona Institute of Science and Technology, Barcelona, Spain;4. Department of Human Genetics, Radboudumc, Nijmegen, The Netherlands;5. Donders Institute for Brain, Cognition and Behaviour, Radboudumc, Nijmegen, The Netherlands;6. Manchester Centre for Genomic Medicine, University of Manchester, Manchester, United Kingdom;7. MedBiotech Hub and Competence Center, Department of Medical Biotechnologies, University of Siena, Siena, Italy;8. Molecular Genetics and Functional Genomics, Ospedale Pediatrico Bambino Gesù, IRCCS, Rome, Italy;9. Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany;10. Centre for Rare Diseases, University Hospital Tübingen, Tübingen, Germany;11. Medical Genetics, University of Siena, Siena, Italy;12. Radboud Institute for Molecular Life Sciences, Radbound University, Nijmegen, The Netherlands;13. Department of Biology and Medical Genetics, Second Faculty of Medicine of Charles University and Motol University Hospital, Prague, Czech Republic;14. Department of Internal Medicine and Radboud Center for Infectious Diseases, Radboudumc, Nijmegen, The Netherlands;15. Department of Genetics and Reference Center for Development Disorders and Intellectual Disabilities, FHU-TRANSLAD and GIMI Institute, Dijon Bourgogne University Hospital, Dijon, France;16. Center of Excellence for Neuropsychiatry, Vincent van Gogh Institute for Psychiatry, Venray, The Netherlands;17. Institute of Rare Diseases Research, Spanish Undiagnosed Rare Diseases Cases Program (SpainUDP) & Undiagnosed Diseases Network International, Instituto de Salud Carlos III, Madrid, Spain;18. Medical Genetics, Azienda Ospedaliero-Universitaria Senese, Siena, Italy;19. MRGM INSERM U1211, University of Bordeaux, Medical Genetics Department, Bordeaux University Hospital, Bordeaux, France;20. Molecular Genetics Laboratory, Medical Genetics Department, Bordeaux University Hospital – Hôpital Pellegrin, Bordeaux, France;21. Department of Genetics, Assistance Publique-Hôpitaux de Paris - Université de Paris, Paris, France;22. INSERM UMR 1141 “NeuroDiderot,” Hôpital Robert Debré, Paris, France;1. Section of Medical Genetics, Children’s Specialist Hospital, King Fahad Medical City, Riyadh, Saudi Arabia;2. Medical Genetics Division, College of Medicine, King Saud University, Riyadh, Saudi Arabia;3. Medical Genetic Division, Department of Pediatrics, King Saud University Medical City, Riyadh, Saudi Arabia;4. Center for Genetics and Inherited Diseases, Taibah University, Almadinah Almunwarah, Saudi Arabia;5. Department of Radiology, King Saud bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Riyadh, Saudi Arabia;6. King Abdullah International Medical Research Center (KAIMRC), King Saud bin Abdulaziz University for Health Sciences, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia;7. Department of Medical Genetics and Mitovasc INSERM 1083, CNRS 6015, Angers University Hospital, Angers, France;8. Division of Pediatric Neurology and Developmental Neuroscience, Department of Pediatrics, Baylor College of Medicine, Houston, TX;9. Texas Children’s Hospital, Houston, TX;10. Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX;11. Centre de Référence des Malformations et Maladies Congénitales du Cervelet, Département de Génétique, AP-HP, Sorbonne Université, Hôpital Trousseau, 75012, Paris, France;12. Developmental Brain Disorders Laboratory, Imagine Institute, INSERM UMR, 1163, F-75015, Paris, France;13. CHU Reims, SFR CAP Sante, EA3801, Reims, France and CHU de Nantes, service de génétique médicale, Nantes, France;14. Child Neurology and Psychiatry Unit, Department of Human Neuroscience, Sapienza-University of Rome, Rome, Italy;15. Department of Precision Medicine, Università della Campania “Luigi Vanvitelli” ,Naples, Italy;16. Telethon Institute of Genetics and Medicine (TIGEM), Pozzuoli, Italy;17. Human Genetics Center, Department of Epidemiology, Human Genetics, and Environmental Sciences, School of Public Health, The University of Texas Health Science Center at Houston, Houston, TX;18. Center of Genetics Diagnosis, Zeynep Kamil Maternity and Children’s Training and Research Hospital, Istanbul, Turkey;19. Department of Medical Genetics, School of Medicine, Marmara University, Istanbul, Turkey;20. Medical Reporting & Genomic Research, CENTOGENE GmbH, Rostock, Germany;21. Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX;22. Department of Pediatrics, Baylor College of Medicine, Houston, TX;23. Dementia Research Institute at King’s College London, The Wohl Institute, 5 Cutcome Rd, London SE59RT, UK;24. Department of Laboratory Medicine, Boston Children’s Hospital, Boston, MA;25. Noor Diagnostics and Discovery, Innovation Cluster, King Abdullah University of Science and Technology (KAUST), Thuwal, Saudi Arabia;26. Genetics and Precision Medicine Department, King Abdullah Specialized Children Hospital (KASCH), King Abdulaziz Medical City (KAMC), Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia;27. College of Applied Medical Sciences, Taibah University, Almadinah Almunwarah, Saudi Arabia |
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| Abstract: | ![]()
PurposeNephrolithiasis (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.MethodsExome sequencing and directed sequencing of the OXGR1 locus were performed in a worldwide NL/NC cohort. Putatively deleterious, rare OXGR1 variants were functionally characterized.ResultsExome 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.ConclusionRare, dominant loss-of-function OXGR1 variants are associated with recurrent calcium oxalate NL/NC disease. |
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| Keywords: | Alpha-ketoglutarate Calcium oxalate Genetics Nephrolithiasis |
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