Daan Viering1, Karl P Schlingmann2, Marguerite Hureaux3,4, Tom Nijenhuis5, Andrew Mallett6,7, Melanie M Y Chan8, André van Beek9, Albertien M van Eerde10, Jean-Marie Coulibaly11, Marion Vallet12, Stéphane Decramer13, Solenne Pelletier14, Günter Klaus15, Martin Kömhoff16, Rolf Beetz17, Chirag Patel7, Mohan Shenoy18, Eric J Steenbergen19, Glenn Anderson20, Ernie M H F Bongers21, Carsten Bergmann22,23, Daan Panneman24, Richard J Rodenburg24, Robert Kleta8,25, Pascal Houillier3,26,27, Martin Konrad2, Rosa Vargas-Poussou3,4,26, Nine V A M Knoers28, Detlef Bockenhauer8,29, Jeroen H F de Baaij30. 1. Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands. 2. Department of General Pediatrics, University Children's Hospital, Münster, Germany. 3. Reference Center for Hereditary Kidney and Childhood Diseases (Maladies rénales héréditaires de l'enfant et de l'adulte [MARHEA]), Paris, France. 4. Department of Genetics, Assistance Publique Hôpitaux de Paris, Hôpital Européen Georges-Pompidou, Paris, France. 5. Department of Nephrology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands. 6. Department of Renal Medicine, Townsville University Hospital, Townsville, Australia. 7. Queensland Conjoint Renal Genetics Service - Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, Australia. 8. Department of Renal Medicine, University College London, London, United Kingdom. 9. Department of Endocrinology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. 10. Genetics Department, University Medical Center Utrecht, Utrecht, The Netherlands. 11. Service of Nephrology, Yves Le Foll Hospital, Saint Brieuc, France. 12. Department of Physiological Functional Investigations, Centre Hospitalier Universitaire de Toulouse, Université Paul Sabatier, Toulouse, France. 13. Pediatric Nephrology, Internal Medicine and Rheumatology, Southwest Renal Rare Diseases Centre (SORARE), University Children's Hospital, Toulouse, France. 14. Department of Nephrology, University Hospital-Lyon Sud, Lyon, France. 15. Kuratorium für Heimdialyse Pediatric Kidney Center, Marburg, Germany. 16. University Children's Hospital, Philipps-University, Marburg, Germany. 17. Johannes Gutenberg Universität Mainz, Zentrum für Kinder- und Jugendmedizin, Mainz, Germany. 18. Department of Paediatric Nephrology, Royal Manchester Children's Hospital, Manchester, United Kingdom. 19. Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands. 20. Department of Pathology, Great Ormond Street Hospital for Children National Health Service (NHS) Foundation Trust, London, United Kingdom. 21. Department of Human Genetics, Radboud University Medical Center, Nijmegen, The Netherlands. 22. Limbach Genetics, Medizinische Genetik Mainz, Prof. Bergmann & Kollegen, Mainz, Germany. 23. Department of Medicine, Division of Nephrology, University Hospital Freiburg, Germany. 24. Radboud Center for Mitochondrial Medicine, Translational Metabolic Laboratory, Department of Pediatrics, Radboud University Medical Center, Nijmegen, The Netherlands. 25. Department of Paediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom. 26. Centre de Recherche des Cordeliers, Sorbonne Université, Institut National de la Santé et de Recherche Médicale (INSERM), Université de Paris, Centre National de la Recherche Scientifique (CNRS), Paris, France. 27. Department of Physiology, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France. 28. Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands. 29. Renal Unit, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom. 30. Department of Physiology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands jeroen.debaaij@radboudumc.nl.
Abstract
BACKGROUND: Gitelman syndrome is the most frequent hereditary salt-losing tubulopathy characterized by hypokalemic alkalosis and hypomagnesemia. Gitelman syndrome is caused by biallelic pathogenic variants in SLC12A3, encoding the Na+-Cl- cotransporter (NCC) expressed in the distal convoluted tubule. Pathogenic variants of CLCNKB, HNF1B, FXYD2, or KCNJ10 may result in the same renal phenotype of Gitelman syndrome, as they can lead to reduced NCC activity. For approximately 10 percent of patients with a Gitelman syndrome phenotype, the genotype is unknown. METHODS: We identified mitochondrial DNA (mtDNA) variants in three families with Gitelman-like electrolyte abnormalities, then investigated 156 families for variants in MT-TI and MT-TF, which encode the transfer RNAs for phenylalanine and isoleucine. Mitochondrial respiratory chain function was assessed in patient fibroblasts. Mitochondrial dysfunction was induced in NCC-expressing HEK293 cells to assess the effect on thiazide-sensitive 22Na+ transport. RESULTS: Genetic investigations revealed four mtDNA variants in 13 families: m.591C>T (n=7), m.616T>C (n=1), m.643A>G (n=1) (all in MT-TF), and m.4291T>C (n=4, in MT-TI). Variants were near homoplasmic in affected individuals. All variants were classified as pathogenic, except for m.643A>G, which was classified as a variant of uncertain significance. Importantly, affected members of six families with an MT-TF variant additionally suffered from progressive chronic kidney disease. Dysfunction of oxidative phosphorylation complex IV and reduced maximal mitochondrial respiratory capacity were found in patient fibroblasts. In vitro pharmacological inhibition of complex IV, mimicking the effect of the mtDNA variants, inhibited NCC phosphorylation and NCC-mediated sodium uptake. CONCLUSION: Pathogenic mtDNA variants in MT-TF and MT-TI can cause a Gitelman-like syndrome. Genetic investigation of mtDNA should be considered in patients with unexplained Gitelman syndrome-like tubulopathies.
BACKGROUND: Gitelman syndrome is the most frequent hereditary salt-losing tubulopathy characterized by hypokalemic alkalosis and hypomagnesemia. Gitelman syndrome is caused by biallelic pathogenic variants in SLC12A3, encoding the Na+-Cl- cotransporter (NCC) expressed in the distal convoluted tubule. Pathogenic variants of CLCNKB, HNF1B, FXYD2, or KCNJ10 may result in the same renal phenotype of Gitelman syndrome, as they can lead to reduced NCC activity. For approximately 10 percent of patients with a Gitelman syndrome phenotype, the genotype is unknown. METHODS: We identified mitochondrial DNA (mtDNA) variants in three families with Gitelman-like electrolyte abnormalities, then investigated 156 families for variants in MT-TI and MT-TF, which encode the transfer RNAs for phenylalanine and isoleucine. Mitochondrial respiratory chain function was assessed in patient fibroblasts. Mitochondrial dysfunction was induced in NCC-expressing HEK293 cells to assess the effect on thiazide-sensitive 22Na+ transport. RESULTS: Genetic investigations revealed four mtDNA variants in 13 families: m.591C>T (n=7), m.616T>C (n=1), m.643A>G (n=1) (all in MT-TF), and m.4291T>C (n=4, in MT-TI). Variants were near homoplasmic in affected individuals. All variants were classified as pathogenic, except for m.643A>G, which was classified as a variant of uncertain significance. Importantly, affected members of six families with an MT-TF variant additionally suffered from progressive chronic kidney disease. Dysfunction of oxidative phosphorylation complex IV and reduced maximal mitochondrial respiratory capacity were found in patient fibroblasts. In vitro pharmacological inhibition of complex IV, mimicking the effect of the mtDNA variants, inhibited NCC phosphorylation and NCC-mediated sodium uptake. CONCLUSION: Pathogenic mtDNA variants in MT-TF and MT-TI can cause a Gitelman-like syndrome. Genetic investigation of mtDNA should be considered in patients with unexplained Gitelman syndrome-like tubulopathies.
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