Karl P Schlingmann1, François Jouret2,3, Kuang Shen4,5,6,7,8, Anukrati Nigam9, Francisco J Arjona10, Claudia Dafinger11,12, Pascal Houillier13,14,15, Deborah P Jones16, Felix Kleinerüschkamp17, Jun Oh18, Nathalie Godefroid19, Mehmet Eltan20, Tülay Güran20, Stéphane Burtey21, Marie-Christine Parotte22, Jens König23, Alina Braun11,12, Caro Bos10, Maria Ibars Serra10, Holger Rehmann24, Fried J T Zwartkruis24, Kirsten Y Renkema9, Karin Klingel25, Eric Schulze-Bahr26, Bernhard Schermer12,27, Carsten Bergmann28,29, Janine Altmüller30, Holger Thiele30, Bodo B Beck31,32,33, Karin Dahan34,35, David Sabatini4,5,6,7, Max C Liebau11,12,33, Rosa Vargas-Poussou36, Nine V A M Knoers37, Martin Konrad23, Jeroen H F de Baaij38. 1. Department of General Pediatrics, University Children's Hospital, Münster, Germany karlpeter.schlingmann@ukmuenster.de jeroen.debaaij@radboudumc.nl. 2. Division of Nephrology, Department of Internal Medicine, University of Liège Hospital, Liège, Belgium. 3. Interdisciplinary Group of Applied Genoproteomics, Cardiovascular Sciences, University of Liège, Liège, Belgium. 4. Whitehead Institute for Biomedical Research, Cambridge, Massachusetts. 5. Department of Biology, Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts. 6. Koch Institute for Integrative Cancer Research, Cambridge, Massachusetts. 7. Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts. 8. Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts. 9. Department of Genetics, Center for Molecular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, The Netherlands. 10. Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands. 11. Department of Pediatrics and Center for Molecular Medicine Cologne, Faculty of Medicine, University of Cologne and University Hospital Cologne, Cologne, Germany. 12. Department II of Internal Medicine and Center for Molecular Medicine Cologne, Faculty of Medicine, University of Cologne and University Hospital Cologne, Cologne, Germany. 13. Cordeliers Research Center, Centre National de la Recherche Scientifique (CNRS), ERL8228, Institut National de la Santé et de la Recherche Médicale (INSERM), Sorbonne University, University of Paris, Paris, France. 14. Department of Physiology, Assistance Publique-Hôpitaux de Paris (AP-HP), European Hospital Georges Pompidou, Paris, France. 15. Reference Center for Hereditary Renal Diseases in Children and Adults (MARHEA), Paris, France. 16. Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee. 17. Department of Pediatric Cardiology, University Children's Hospital, Münster, Germany. 18. Department of Pediatrics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany. 19. Division of Pediatric Nephrology, Saint-Luc University Clinics, Catholic University of Louvain, Brussels, Belgium. 20. Department of Pediatric Endocrinology and Diabetes, School of Medicine, Marmara University, Istanbul, Turkey. 21. Center for Nephrology and Renal Transplantation, Assistance Publique-Hôpitaux de Marseille, Aix-Marseille University, Marseille, France. 22. Division of Nephrology-Dialysis, Department of Internal Medicine, CHR Verviers East Belgium, Verviers, Belgium. 23. Department of General Pediatrics, University Children's Hospital, Münster, Germany. 24. Department of Molecular Cancer Research, Center for Molecular Medicine, Oncode Institute, University Medical Center Utrecht, Utrecht, The Netherlands. 25. Cardiopathology, Institute for Pathology and Neuropathology, University Hospital Tübingen, Tübingen, Germany. 26. Institute for Genetics of Heart Diseases (IfGH), Department of Cardiovascular Medicine, University Hospital Münster, Münster, Germany. 27. CECAD, Faculty of Medicine, University of Cologne and University Hospital Cologne, Cologne, Germany. 28. Limbach Genetics, Medizinische Genetik Mainz, Mainz, Germany. 29. Division of Nephrology, Department of Medicine, University Hospital Freiburg, Breisgau, Germany. 30. Cologne Center for Genomics, University of Cologne, Cologne, Germany. 31. Institute of Human Genetics, University Hospital Cologne and University of Cologne, Faculty of Medicine, Cologne, Germany. 32. Center for Molecular Medicine Cologne, University of Cologne, Faculty of Medicine, University Hospital Cologne, Cologne, Germany. 33. Center for Rare Diseases, Medical Faculty, University of Cologne and University Hospital Cologne, Cologne, Germany. 34. Center of Human Genetics, Gosselies, Belgium. 35. Division of Nephrology, Saint-Luc University Clinics, Catholic University of Louvain, Brussels, Belgium. 36. Department of Genetics, AP-HP, European Hospital Georges Pompidou, Paris, France. 37. Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. 38. Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands karlpeter.schlingmann@ukmuenster.de jeroen.debaaij@radboudumc.nl.
Abstract
BACKGROUND: Over the last decade, advances in genetic techniques have resulted in the identification of rare hereditary disorders of renal magnesium and salt handling. Nevertheless, approximately 20% of all patients with tubulopathy lack a genetic diagnosis. METHODS: We performed whole-exome and -genome sequencing of a patient cohort with a novel, inherited, salt-losing tubulopathy; hypomagnesemia; and dilated cardiomyopathy. We also conducted subsequent in vitro functional analyses of identified variants of RRAGD, a gene that encodes a small Rag guanosine triphosphatase (GTPase). RESULTS: In eight children from unrelated families with a tubulopathy characterized by hypomagnesemia, hypokalemia, salt wasting, and nephrocalcinosis, we identified heterozygous missense variants in RRAGD that mostly occurred de novo. Six of these patients also had dilated cardiomyopathy and three underwent heart transplantation. We identified a heterozygous variant in RRAGD that segregated with the phenotype in eight members of a large family with similar kidney manifestations. The GTPase RagD, encoded by RRAGD, plays a role in mediating amino acid signaling to the mechanistic target of rapamycin complex 1 (mTORC1). RagD expression along the mammalian nephron included the thick ascending limb and the distal convoluted tubule. The identified RRAGD variants were shown to induce a constitutive activation of mTOR signaling in vitro. CONCLUSIONS: Our findings establish a novel disease, which we call autosomal dominant kidney hypomagnesemia (ADKH-RRAGD), that combines an electrolyte-losing tubulopathy and dilated cardiomyopathy. The condition is caused by variants in the RRAGD gene, which encodes Rag GTPase D; these variants lead to an activation of mTOR signaling, suggesting a critical role of Rag GTPase D for renal electrolyte handling and cardiac function.
BACKGROUND: Over the last decade, advances in genetic techniques have resulted in the identification of rare hereditary disorders of renal magnesium and salt handling. Nevertheless, approximately 20% of all patients with tubulopathy lack a genetic diagnosis. METHODS: We performed whole-exome and -genome sequencing of a patient cohort with a novel, inherited, salt-losing tubulopathy; hypomagnesemia; and dilated cardiomyopathy. We also conducted subsequent in vitro functional analyses of identified variants of RRAGD, a gene that encodes a small Rag guanosine triphosphatase (GTPase). RESULTS: In eight children from unrelated families with a tubulopathy characterized by hypomagnesemia, hypokalemia, salt wasting, and nephrocalcinosis, we identified heterozygous missense variants in RRAGD that mostly occurred de novo. Six of these patients also had dilated cardiomyopathy and three underwent heart transplantation. We identified a heterozygous variant in RRAGD that segregated with the phenotype in eight members of a large family with similar kidney manifestations. The GTPase RagD, encoded by RRAGD, plays a role in mediating amino acid signaling to the mechanistic target of rapamycin complex 1 (mTORC1). RagD expression along the mammalian nephron included the thick ascending limb and the distal convoluted tubule. The identified RRAGD variants were shown to induce a constitutive activation of mTOR signaling in vitro. CONCLUSIONS: Our findings establish a novel disease, which we call autosomal dominant kidney hypomagnesemia (ADKH-RRAGD), that combines an electrolyte-losing tubulopathy and dilated cardiomyopathy. The condition is caused by variants in the RRAGD gene, which encodes Rag GTPase D; these variants lead to an activation of mTOR signaling, suggesting a critical role of Rag GTPase D for renal electrolyte handling and cardiac function.
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