Gitelman-Like Syndrome Caused by Pathogenic Variants in mtDNA.
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Viering Daan, Schlingmann Karl P, Hureaux Marguerite, Nijenhuis Tom, Mallett Andrew, Chan Melanie M Y, van Beek André, van Eerde Albertien M, Coulibaly Jean-Marie, Vallet Marion, Decramer Stéphane, Pelletier Solenne, Klaus Günter, Kömhoff Martin, Beetz Rolf, Patel Chirag, Shenoy Mohan, Steenbergen Eric J, Anderson Glenn, Bongers Ernie M H F, Bergmann Carsten, Panneman Daan, Rodenburg Richard J, Kleta Robert, Houillier Pascal, Konrad Martin, Vargas-Poussou Rosa, Knoers Nine V A M, Bockenhauer Detlef, de Baaij Jeroen H F, Genomics England Research Consortium
Аннотация
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.