[en] [en] INTRODUCTION: Variants in the Ras-related GTPase D (RRAGD) gene have been associated with autosomal dominant kidney hypomagnesemia (ADKH) characterized by hypokalemia, nephrocalcinosis, and dilated cardiomyopathy (DCM). RRAGD, which encodes for the RagD protein, is involved in the activation of the mechanistic target of rapamycin complex 1 (mTORC1). Owing to the limited characterization of patients' phenotypes, the understanding of RRAGD-associated ADKH (ADKH-RRAGD) remains incomplete. Consequently, available treatment strategies are primarily symptomatic and insufficient.
METHODS: In the present case series, 13 new patients and 3 novel RRAGD variants, that is, p.(Ser77Phe), p.(Thr91Ile), and p.(Ile100Arg), are described. To assess the pathogenicity of the novel variants, an in vitro assay of mTORC1 activity was performed. In addition, the clinical response to diuretics (furosemide and thiazide, n = 4) and Na+-glucose cotransporter 2 (SGLT2) inhibitor, dapagliflozin (n = 6) was evaluated in patients carrying the RRAGD p.(Thr97Pro) variant during routine.
RESULTS: The patients presented with kidney tubulopathies, including hypomagnesemia, hypercalciuria, and nephrocalcinosis. Five patients also exhibited DCM. In vitro assays demonstrated constitutive activation of noncanonical mTORC1 signaling caused by the p.(Ser77Phe) and p.(Ile100Arg) variants. Clinically, patients remained sensitive to diuretic challenges, whereas dapagliflozin treatment increased serum magnesium (Mg2+) levels by 0.04 mM but exacerbated hypokalemia.
CONCLUSION: To date, 37 patients with ADKH-RRAGD have been identified. Kidney tubulopathy is the most prominent feature within the phenotypic spectrum of ADKH-RRAGD. Molecularly, constitutive activation of noncanonical mTORC1 is present in most RRAGD variants. From a therapeutic perspective, dapagliflozin may increase serum Mg2+ levels in patients with RRAGD variants.
Disciplines :
Urology & nephrology
Author, co-author :
Adella, Anastasia; Department of Medical BioSciences, Radboudumc, Nijmegen, The Netherlands
Jouret, François ; Université de Liège - ULiège > Département des sciences cliniques > Néphrologie
Madariaga, Leire; Pediatric Nephrology Department, Biobizkaia Health Research Institute, University of the Basque Country, CIBERDEM/CIBERER, Cruces University Hospital, Barakaldo, Spain
Leermakers, Pieter A; Department of Medical BioSciences, Radboudumc, Nijmegen, The Netherlands
Arango, Pedro; Pediatric Nephrology and Renal Transplant Department, Hospital Sant Joan de Déu, Barcelona, Spain
Ariceta, Gema; Pediatric Nephrology Department, Vall d'Hebron Hospital, Autonomous University of Barcelona, Barcelona, Spain
Beck, Bodo B; Faculty of Medicine, Center for Molecular Medicine Cologne, Institute of Human Genetics, University Hospital Cologne and University of Cologne, Cologne, Germany ; Medical Faculty, Center for Rare Diseases, University of Cologne and University Hospital Cologne, Cologne, Germany
Bjerre, Anna; Division of Pediatric and Adolescent Medicine, Department of Transplantation and Specialized Medicine, Oslo University Hospital, Oslo, Norway ; Institute of Clinical Medicine, University of Oslo, Oslo, Norway
Bockenhauer, Detlef; Department of Paediatric Nephrology, UZ Leuven and Cellular and Molecular Physiology, KUL, Leuven, Belgium ; Department of Renal Medicine, University College London and Paediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
Coccia, Paula; Division of Pediatric Nephrology, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
Dhamija, Radhika; Department of Clinical Genomics, Mayo Clinic, Rochester, Minnesota, USA
de Frutos, Fernando; Heart Failure and Inherited Cardiac Diseases Unit, Department of Cardiology, Hospital Universitari de Bellvitge, L'Hospitalet de Llobregat, Barcelona, Spain ; Bioheart Group, Cardiovascular, Respiratory and Systemic Diseases and cellular aging Program, Institut d'Investigació Biomèdica de Bellvitge (IDIBELL), L'Hospitalet de Llobregat, Spain
Garcia-Castano, Alejandro; Biobizkaia Health Research Institute, CIBERDEM/CIBERER, Barakaldo, Spain
van Katwijk, Sara B; Department of Medical BioSciences, Radboudumc, Nijmegen, The Netherlands
Lucas, Jesus; Pediatric Nephrology Department, General University Hospital of Castellón, Castellón, Spain
Möller, Thomas; Department of Paediatric Cardiology, Division of Paediatric and Adolescent Medicine, Oslo University Hospital, Oslo, Norway
Müller, Dominik; Department of Pediatric Gastroenterology, Nephrology and Metabolic Diseases, Charité, University Medicine, Berlin, Germany
Pinto E Vairo, Filippo; Department of Clinical Genomics, Center for Individualized Medicine, Mayo Clinic, Rochester, Minnesota, USA
Raki, Melinda; Department of Pathology, Oslo University Hospital, Oslo, Norway
Rips, Jonathan; Department of Genetics, Hadassah Medical Center, Jerusalem, Israel ; Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
Schlingmann, Karl Peter; Department of General Pediatrics, University Children's Hospital Münster, Münster, Germany
Venselaar, Hanka; Department of Medical BioSciences, Radboudumc, Nijmegen, The Netherlands
Machado Bressan Wilke, Matheus Vernet; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri, USA
Nijenhuis, Tom; Department of Nephrology, Radboudumc, Nijmegen, The Netherlands
Hoenderop, Joost; Department of Medical BioSciences, Radboudumc, Nijmegen, The Netherlands
de Baaij, Jeroen; Department of Medical BioSciences, Radboudumc, Nijmegen, The Netherlands
ERC - European Research Council Nierstichting NWO - Nederlandse Organisatie voor Wetenschappelijk Onderzoek Eusko Jaurlaritza ISCIII - Instituto de Salud Carlos III
Funding text :
We would like to thank the Radboudumc Technology Center Microscopy for the use of their microscopy facilities. This work was financially supported by the IMAGEN (IMplementation of Advancements in GENetic Kidney Disease) project, which is cofunded by the PPP Allowance made available by Health\u223CHolland, Top Sector Life Sciences & Health, to stimulate public-private partnerships (LSHM20009) and the Dutch Kidney Foundation (20OP + 018). In addition, this work was funded by the European Research Council grant 101040682 (IN-THE-KIDNEY) and Netherlands Organization for Scientific Research grants OCENW.M.21.022 and VIDI 391 09150172110040 (IMAGE-THE-KIDNEY). The study of families 4 to 6 was financially supported by the grant PI21/01419 from the National Institute of Health Carlos III (Spain) and the grant IT1739-22 from the Department of Education of the Basque Government (Spain). BBB was supported by the K\u00F6ln-Fortune Programm der Medizinischen Fakult\u00E4t (grant KF183/2022). The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the funding institutions. The variants described in this study have been submitted to ClinVar.This work was financially supported by the IMAGEN (IMplementation of Advancements in GENetic Kidney Disease) project, which is cofunded by the PPP Allowance made available by Health\u223CHolland, Top Sector Life Sciences & Health, to stimulate public-private partnerships (LSHM20009) and the Dutch Kidney Foundation (20OP + 018). In addition, this work was funded by the European Research Council grant 101040682 (IN-THE-KIDNEY) and Netherlands Organization for Scientific Research grants OCENW.M.21.022 and VIDI 391 09150172110040 (IMAGE-THE-KIDNEY). The study of families 4 to 6 was financially supported by the grant PI21/01419 from the National Institute of Health Carlos III (Spain) and the grant IT1739-22 from the Department of Education of the Basque Government (Spain). BBB was supported by the K\u00F6ln-Fortune Programm der Medizinischen Fakult\u00E4t (grant KF183/2022). The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the funding institutions.
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