Gitelman-Like Syndrome Caused by Pathogenic Variants in mtDNA.

Abstract

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 <i>SLC12A3,</i> encoding the Na⁺-Cl^- cotransporter (NCC) expressed in the distal convoluted tubule. Pathogenic variants of <i>CLCNKB</i>, <i>HNF1B</i>, <i>FXYD2</i>, or <i>KCNJ10</i> 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. We identified mitochondrial DNA (mtDNA) variants in three families with Gitelman-like electrolyte abnormalities, then investigated 156 families for variants in <i>MT-TI</i> and <i>MT-TF</i>, 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. Genetic investigations revealed four mtDNA variants in 13 families: m.591C>T (<i>n</i>=7), m.616T>C (<i>n</i>=1), m.643A>G (<i>n</i>=1) (all in <i>MT-TF</i>), and m.4291T>C (<i>n</i>=4, in <i>MT-TI</i>). 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 <i>MT-TF</i> 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. <i>In vitro</i> pharmacological inhibition of complex IV, mimicking the effect of the mtDNA variants, inhibited NCC phosphorylation and NCC-mediated sodium uptake. Pathogenic mtDNA variants in <i>MT-TF</i> and <i>MT-TI</i> can cause a Gitelman-like syndrome. Genetic investigation of mtDNA should be considered in patients with unexplained Gitelman syndrome-like tubulopathies.