ESPN 54th Annual Meeting

ESPN 2022

Gitelman-Like Syndrome Caused by Pathogenic Variants in mtDNA
SCHLINGMANN KARL 1 Viering Daan 2 Hureaux Marguerite 3 Nijenhius Tom 4 Klaus Günter 5 Komhoff Martin 5 Beetz Rolf 6 Shenoy Mohan 7 Kleta Robert 8 Houillier Pascal 10 Konrad Martin 1 Vargas-Poussou Rosa 9 Knoers Nine 11 Bockenhauer Detlef 8 deBaaij Jeroen 2

2- Radboud university medical center, Radboud Institute for Molecular Life Sciences, Department of Physiology, Nijmegen, the Netherlands.
3- Reference Center for Hereditary Kidney and Childhood Diseases (MARHEA), Paris, France
4- Radboud university medical center, Radboud Institute for Molecular Life Sciences, Department of Nephrology, Nijmegen, the Netherlands.
5- Kuratorium für Heimdialyse Pediatric Kidney Center, Marburg, Germany
6- Johannes Gutenberg Universität Mainz, Zentrum für Kinder- und Jugendmedizin, Mainz, Germany
7- Department of Paediatric Nephrology, Royal Manchester Children’s Hospital, Manchester, United Kingdom
8- Department of Paediatric Nephrology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, United Kingdom
9- Centre de Recherche des Cordeliers, Sorbonne Université, INSERM, Université de Paris, CNRS, Paris, France
10- Department of Physiology, Assistance Publique-Hôpitaux de Paris, Hôpital Européen Georges Pompidou, Paris, France
11- Department of Genetics, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands

Gitelman syndrome (GS) is the most frequent hereditary salt-losing tubulopathy characterized by hypokalemic alkalosis and hypomagnesemia. It is caused by biallelic pathogenic variants in SLC12A3, encoding the Na+-Cl- cotransporter (NCC) expressed in the distal convoluted tubule. However, for approximately 10 percent of GS patients, the genotype still remains unknown.

Material and methods:

Mitochondrial DNA variants were identified in three families with Gitelman-like electrolyte abnormalities, then 156 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 and mitochondrial dysfunction induced in HEK293 cells to assess the effect on NCC-mediated 22Na+ transport.


Genetic investigations revealed four mtDNA variants in near homoplasmic state in 13 families. 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.


Pathogenic mtDNA variants in MT-TF and MT-TI cause a Gitelman-like syndrome. Genetic investigation of mtDNA should be considered in patients with unexplained Gitelman syndrome-like tubulopathies.