The most common genetic salt-losing tubulopathy is Gitelman syndrome, characterized by hypokalemic alkalosis and hypomagnesemia. Biallelic pathogenic mutations in SLC12A3, which encodes the Na+-Cl cotransporter (NCC) expressed in the distal convoluted tubule, cause Gitelman syndrome. In addition, pathogenic mutations of CLCNKB, HNF1B, FXYD2, or KCNJ10 might cause the same renal phenotype as Gitelman syndrome due to decreased NCC activity. The genotype of around 10% of individuals with a Gitelman syndrome phenotype is unknown.

For a study, researchers found mitochondrial DNA (mtDNA) variations in 3 families with Gitelman-like electrolyte abnormalities. They then looked for variants in MT-TI and MT-TF, which encode the transfer RNAs for phenylalanine and isoleucine, in 156 families. In inpatient fibroblasts, mitochondrial respiratory chain activity was evaluated. Mitochondrial dysfunction was produced in NCC-expressing HEK293 cells to see how it affected thiazide-sensitive 22Na+ transport.

Four mtDNA variations were discovered 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). In afflicted individuals, the variants were nearly homoplasmic. Except for m.643A>G, which was identified as a variation of unknown significance, other variants were designated as pathogenic. Notably, afflicted members of 6 families with an MT-TF mutation also had progressive chronic renal disease. In patient fibroblasts, oxidative phosphorylation complex IV dysfunction, and decreased maximum mitochondrial respiratory capacity were discovered. In vitro pharmacological suppression of complex IV decreased NCC phosphorylation and NCC-mediated salt absorption, replicating the action of the mtDNA variations. 

Gitelman-like syndrome can be caused by pathogenic mtDNA mutations in MT-TF and MT-TI. Therefore, in patients with unexplained Gitelman syndrome-like tubulopathies, mtDNA genetic testing should be explored.