Gitelman-Like Syndrome Caused by Pathogenic Variants in mtDNA

Genomics England Res Consortium, Daan Viering, Karl P. Schlingmann, Marguerite Hureaux, Tom Nijenhuis, Andrew Mallett, Melanie M. Y. Chan, Andre van Beek, Albertien M. van Eerde, Jean-Marie Coulibaly, Marion Vallet, Stephane Decramer, Solenne Pelletier, Gunter Klaus, Martin Komhoff, Rolf Beetz, Chirag Patel, Mohan Shenoy, Eric J. Steenbergen, Glenn AndersonErnie M. H. F. Bongers, Carsten Bergmann, Daan Panneman, Richard J. Rodenburg, Robert Kleta, Pascal Houillier, Martin Konrad, Rosa Vargas-Poussou, Nine V. A. M. Knoers, Detlef Bockenhauer, Jeroen H. F. de Baaij*

*Bijbehorende auteur voor dit werk

OnderzoeksoutputAcademicpeer review

15 Citaten (Scopus)
61 Downloads (Pure)


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. Patho-genic 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 electro-lyte abnormalities, then investigated 156 families for variants in MT-TI and MT-TF, which encode the trans-fer 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 Na-22(+) 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.

Originele taal-2English
Pagina's (van-tot)305-325
Aantal pagina's44
TijdschriftJournal of the American Society of Nephrology
Nummer van het tijdschrift2
Vroegere onlinedatum19-jan.-2022
StatusPublished - feb.-2022

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