Gitelman-like syndrome caused by pathogenic variants in mtDNA

Viering, Daan, Schlingmann, Karl-Peter, Hureaux, Marguerite, Nijhenhuis, Tom, Mallett, Andrew, Chan, Melanie MY, van Beek, André, van Eerde, Albertien M, Coulibaly, Jean-Marie, Vallet, Marion, Decramer, Stéphane, Pelletier, Solenne, Klaus, Günter, Komhoff, Martin, Beetz, Rolf, Patel, Chirag, Shenoy, Mohan, Steenbergen, Eric J., Anderson, Glenn, Bongers, Ernie M.H.F., Bermann, Carsten, Penneman, Daan, Rodenburg, Richard J., Kleta, Robert, Houillier, Pascal, Konrad, Martin, Vargas-Poussou, Rosa, Knoers, Nine, Bockenhauer, Detlef, de Baaij, Jeroen, and Genomics England Research Consortium, (2022) Gitelman-like syndrome caused by pathogenic variants in mtDNA. Journal of the American Society of Nephrology, 33 (2). pp. 305-325.

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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. Pathogenic 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 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.

Item ID: 73197
Item Type: Article (Research - C1)
ISSN: 1533-3450
Keywords: Epithelial sodium transport, genetic renal disease, Na+ transport, ion transport, mitocondria, Gitelman syndrome, blood pressure, chronic kidney disease, chronic kidney failure, sodium-chloride cotransporter
Copyright Information: Copyright © 2022 by the American Society of Nephrology
Additional Information:

All members of the Genomics England Research Consortium are listed at the end of the article

Date Deposited: 29 Mar 2022 02:38
FoR Codes: 31 BIOLOGICAL SCIENCES > 3105 Genetics > 310509 Genomics @ 50%
32 BIOMEDICAL AND CLINICAL SCIENCES > 3202 Clinical sciences > 320214 Nephrology and urology @ 50%
SEO Codes: 20 HEALTH > 2001 Clinical health > 200101 Diagnosis of human diseases and conditions @ 100%
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