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Abstract: TH-OR22

Gitelman Syndrome Phenocopy Caused by Pathogenic Variants in Mitochondrial DNA

Session Information

Category: Fluid, Electrolyte, and Acid-Base Disorders

  • 902 Fluid, Electrolyte, and Acid-Base Disorders: Clinical


  • Viering, Daan, Radboudumc Afdeling Fysiologie, Nijmegen, Gelderland, Netherlands
  • Schlingmann, Karl P., University children's hospital, Münster, department of General Pediatrics, Münster, Germany
  • Hureaux, Marguerite, Assistance Publique - Hopitaux de Paris, Paris, Île-de-France, France
  • Nijenhuis, Tom, Radboudumc, Department of Nephrology, Nijmegen, Gelderland, Netherlands
  • Vargas-Poussou, Rosa, Assistance Publique - Hopitaux de Paris, Paris, Île-de-France, France
  • Knoers, Nine V., University Medical Center Groningen, Department of Genetics, Groningen, Groningen, Netherlands
  • Bockenhauer, Detlef, Great Ormond Street Hospital for Children NHS Foundation Trust, London, London, United Kingdom
  • De Baaij, Jeroen H.F., Radboudumc Afdeling Fysiologie, Nijmegen, Gelderland, Netherlands

Group or Team Name

  • Molecular Physiology

Gitelman syndrome (GS) is the most frequent hereditary salt-losing tubulopathy and is characterized by hypokalemic alkalosis and hypomagnesemia. GS is caused by biallelic pathogenic variants in SLC12A3, encoding the Na+-Cl- cotransporter (NCC) expressed in the distal convoluted tubule. Pathogenic variants in CLCNKB, HNF1B, FXYD2 or KCNJ10 may result in renal phenocopies of GS, as they can lead to reduced NCC activity. Nevertheless, ±10% of patients with a GS phenotype remain genetically unsolved.


After identification of mitochondrial DNA (mtDNA) variants in three families with GS-like electrolyte abnormalities, 155 families were investigated for variants in MT-TI and MT-TF, encoding the transfer RNAs for phenylalanine and isoleucine. Mitochondrial respiratory chain function was assessed in patient fibroblasts. In NCC-expressing HEK293 cells, mitochondrial dysfunction was induced to assess the effect on thiazide-sensitive 22Na+ transport.


Genetic investigations revealed four mtDNA variants in 12 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=3, in MT-TI). Variants segregated with the phenotype and were near homoplasmic in affected individuals. Importantly, affected members of six families with an MT-TF variant additionally suffered from progressive chronic kidney disease (CKD). Kidney biopsies in two affected individuals showed abnormal mitochondria, especially in the distal tubule. Maximal mitochondrial respiratory capacity was reduced in patient fibroblasts, caused by dysfunction of oxidative phosphorylation complex IV. In vitro pharmacological inhibition of complex IV, mimicking the effect of the mtDNA variants, demonstrated an inhibitory effect on NCC phosphorylation and NCC-mediated sodium uptake.


Pathogenic mtDNA variants in MT-TF and MT-TI can cause a GS phenocopy. Genetic investigation of mtDNA should be considered in patients with unexplained GS-like tubulopathies. Moreover, pathogenic variants in MT-TF confer a significant risk for the development of CKD.


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