Gitelman-Like Syndrome Caused by Pathogenic Variants in mtDNA

Abstract

Background: Gitelman syndrome (GS) is the most frequent hereditary salt-losing tubulopathy characterized by hypokalemic alkalosis and hypomagnesemia. GS is caused by biallelic pathogenic variants in SLC12A3, encoding the Na+-Cl- cotransporter (NCC) expressed in the distal convoluted tubule. Pathogenic variants of CLCNKB, HNF1B, FXYD2, or KCNJ10 may result in the same renal phenotype of GS, as they can lead to reduced NCC activity. For approximately 10 percent of patients with a GS phenotype, the genotype is unknown. Methods: We identified mitochondrial DNA (mtDNA) variants in three families with GS-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 reduced maximal mitochondrial respiratory capacity 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 GS-like syndrome. Genetic investigation of mtDNA should be considered in patients with unexplained GS-like tubulopathies.

Mechanisms of ion transport regulation by HNF1β in the kidney: beyond transcriptional regulation of channels and transporters

“…Given the high energetic demand of the kidneys, the energy deficiency triggered by HNF1β defects might influence transport processes in the PT, and potentially TAL and DCT-mediated transport of Mg 2+ , Ca 2+ , and K + . Indeed, mutations in the mitochondrial DNA were recently demonstrated to cause a Gitelman-like phenotype of hypomagnesemia and hypokalemia [ 82 ].…”

The genetic spectrum of Gitelman(-like) syndromes

“…Only recently, these findings were confirmed in 10 additional families with a maternal inheritance pattern [17 ▪▪ ]. A large European collaboration demonstrated that mitochondrial DNA variants in MT-TI and MT-TF are causative for a Gitelman-like syndrome [17 ▪▪ ]. Interestingly, the MT-TF mutations were also associated with chronic kidney disease, whereas patients with MT-TI mutations showed a preserved kidney function [17 ▪▪ ].…”

“…In patient fibroblasts, the identified MT-TI and MT-TF mutations were demonstrated to reduce mitochondrial function [17 ▪▪ ]. Although the exact mechanisms remain unclear, pharmacological inhibition of complex IV, mimicking the effect of the mtDNA variants, inhibited NCC phosphorylation and NCC-mediated Na + uptake [17 ▪▪ ]. However, it should be noted that only specific MT-TI and MT-TF mutations are associated with a Gitelman-like phenotype.…”

“…In recent years, several seminal discoveries have been made to resolve the missing heritability in Gitelman syndrome [16 ▪ ,17 ▪▪ ]. This review, therefore, provides an overview of all known genetic causes of Gitelman-like syndromes.…”

Clinical and Genetic Characterization of Patients with Bartter and Gitelman Syndrome

“…So far, seven genes (namely, SCL12A1 , KCNJ1 , CLCNKA , CLCNKB , BSND , MAGED2 , SLC12A3 ) have been recognized as responsible for BS and GS, accounting for about 70–80% of genetically confirmed cases [ 1 , 5 , 14 ]. Very recently, mutations in mitochondrial DNA were reported in association with Gitelman-like phenotypes, thus expanding the genetic background of these disorders to additional patterns of inheritance [ 15 ]. In recent years, rapidly decreasing costs and turnaround time led next-generation sequencing (NGS) to spread in diagnostics of inherited tubulopathies, including BS and GS [ 13 , 16 ].…”