Gitelman-Like Syndrome Caused by Pathogenic Variants in mtDNA
Viering, Daan; Schlingmann, Karl-Peter; Hureaux, Marguerite; Nijenhuis, Tom; Mallett, Andrew; Chan, Melanie; van Beek, Andre; van Eerde, Albertien; Coulibaly, Jean-Marie; Vallet, Marion; Decramer, Stéphane; Pelletier, Solenne; Klaus, Günter; Kömhoff, Martin; Beetz, Rolf; Patel, Chirag; Shenoy, Mohan; Steenbergen, Eric; Anderson, Glenn; Bongers, Ernie; Bergmann, Carsten; Panneman, Daan; Rodenburg, Richard; Kleta, Robert; Houillier, Pascal; Konrad, Martin; Vargas-Poussou, Rosa; Bockenhauer, Detlef; de Baaij, Jeroen
(2022) Journal of the American Society of Nephrology, volume 33, issue 2, pp. 305 - 325
(Article)
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 1-Cl 2 cotransporter (NCC) expressed in the distal convoluted tubule. Pathogenic variants of CLCNKB, HNF1B, FXYD2, or KCNJ10 may result in
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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 1 transport. Results Genetic investigations revealed four mtDNA variants in 13 families: m.591C>T (n57), m.616T>C (n51), m.643A>G (n51) (all in MT-TF), and m.4291T>C (n54, 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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Keywords: blood pressure, chronic kidney disease, chronic kidney failure, epithelial sodium transport, genetic renal disease, Gitelman-s syndrome, human genetics, ion transport, mitochondria, Na transport, Nephrology, Journal Article
ISSN: 1046-6673
Publisher: American Society of Nephrology
Note: Funding Information: Several authors of this publication are members of the European Reference Network for Rare Kidney Diseases (ERKNet)—Project ID No. 739532. Andrew Mallett was supported by an Royal Australasian College of Physicians Jacquot Research Establishment Fellowship and an Metro North Hospital and Health Service Clinical Research Fellowship. Funding Information: This work was financially supported by the IMAGEN project which is cofunded by the PPP Allowance made available by Health~Holland, Top Sector Life Sciences & Health, to stimulate public-private partnerships (IMplementation of Advancements in GENetic Kidney Disease, LSHM20009) and the Dutch Kidney Foundation (Nierstichting) (20OP1018). Additionally, we received support from ZonMW under the frame of EJPRD, the European Joint Programme on Rare Diseases (EJPRD2019-40). This project has received funding from the European Union’s Horizon 2020 Research and Innovation Programme under the EJP RD COFUND-EJP N° 825575 and the Netherlands Organization for Scientific Research (Nederlandse Organisatie voor Wetenschappelijk Onderzoek) (NWO Veni 016.186.012). The 100,000 Genomes Project is managed by Genomics England Limited (a wholly owned company of the Department of Health and Social Care). The 100,000 Genomes Project is funded by the National Institute for Health Research and NHS England. The Wellcome Trust, Cancer Research UK, and the Medical Research Council have also funded research infrastructure of the 100,000 Genomes Project. Funding Information: C. Bergmann reports Ownership Interest in Medizinische Genetik Mainz; Research Funding from Limbach; Honoraria from Alexion, Atheneum, Kyowa Kirin, Merck, Otsuka, PTC, Sanofi; Scientific Advisor or Membership via medical and scientific board of German PKD Foundation, advisory boards of PTC, and Alexion; and Other Interests/Relationships as member of the kidney community (GPN, DGfN, ERA/EDTA, IPNA, ESPN, ASN). D. Bockenhauer reports Consultancy Agreements with Advicenne, Avrobio, Otsuka, Sanofi; Honoraria from Advicenne, Record-ati; and Scientific Advisor or Membership as associate editor of Pediatric Nephrology, NDT, and editorial board of JASN. P. Houillier reports Consultancy Agreements with Amgen, Shire/Takeda, KyowaKirin; Research Funding from Amgen, Takeda/Shire; Honoraria from KyowaKirin, Takeda/Shire; Scientific Advisor or Membership with NCCR Kidney.CH (Switzerland); Member of the editorial board of JASN; and Other Interests/Relationships via working group on calcium and bone for the European Society of Endocrinology. G. Klaus reports Consultancy Agreements: Fresenius Medical Care as Oral presentation at ESPN 2021, Vifor Fresenius Medical Care Renal Pharma Ltd (stopped 2020); Honoraria from Fresenius Medical Care for Oral presentation at ESPN 2021, Vifor Fresenius Medical Care Renal Pharma Ltd (stopped 2020); Other Interests/Relationships with KfH-Kuratorium fu€r Dialyse und Nierentransplantation, and Gesellschaft fu€r P€adiatrische Nephrologie (GPN) Speaker for medical education. N. Knoers reports Honoraria from ErasmusMC, The Netherlands, for SEP evaluation; Scientific Advisor or Membership via different research advisory committees without any financial compensation; and Other Interests/Relationships as Chair board ERA-EDTA WGIKD, Chair Task Force Molecular Diagnostics, European Reference Network of Rare Renal Diseases, ERKNET. M. Konrad reports Consultancy Agreements with Otsuka. A. Mallett reports Research Funding from Otsuka, Sanofi-Genzyme; Scientific Advisor or Membership with Otsuka; Other Interests/ Relationships as Local Site Trial Investigator for Achillion, Dicerna, Novo-tech, Reata, Sanofi-Genzyme; and Research Fellowships with RACP Jac-quot Research Establishment Fellowship and MNHHS Clinical Research Fellowship. T. Nijenhuis reports Research Funding from the Dutch Kidney Foundation, Radboudumc; Scientific Advisor or Membership via Scientific board of the Dutch Society for Nephrology, Scientific advisory board of the Dutch Kidney Foundation, Co-chair of the Tubulopathies Expert Working Group, European Rare Kidney Disorders Network (ERKNet), and Board member of ERA-EDTA Working Group Inherited Kidney Disorders. A. van Eerde reports Other Interests/Relationships with ERA-EDTA, Working Group Inherited Kidney Diseases Board, ERKNet, WG chair receives funding from the Dutch Kidney Foundation. R. Vargas-Poussou reports Scientific Advisor or Membership with Advicenne. J. de Baaij reports Research Funding from the Dutch Kidney Foundation and the Dutch Diabetes Research Foundation. All remaining authors have nothing to disclose. Publisher Copyright: ß 2022 by the American Society of Nephrology
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