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Gitelman‐like syndrome caused by pathogenic variants in mitochondrial DNA
Author(s) -
Baaij Jeroen H. F.,
Viering Daan,
Schlingmann Karl P.,
Hureaux Marguerite,
Nijenhuis Tom,
Knoers Nine V.,
Vargas Poussou Rosa,
Bockenhauer Detlef
Publication year - 2022
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2022.36.s1.r2172
Subject(s) - gitelman syndrome , tubulopathy , distal convoluted tubule , bartter syndrome , mitochondrial dna , biology , genetics , compound heterozygosity , medicine , endocrinology , microbiology and biotechnology , hypomagnesemia , chemistry , reabsorption , hypokalemia , mutation , gene , kidney , organic chemistry , magnesium
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 in CLCNKB, HNF1B, FXYD2 or KCNJ10 may result in renal phenocopies of Gitelman syndrome, as they can lead to reduced NCC activity. Nevertheless, ±10% of patients with a Gitelman syndrome phenotype remain genetically unsolved. After identification of mitochondrial DNA (mtDNA) variants in three families with Gitelman syndrome‐like electrolyte abnormalities, 156 families were investigated for variants in MT‐TI and MT‐TF , encoding the transfer RNAs for phenylalanine and isoleucine. Mitochondrial respiratory chain function was assessed in patient fibroblasts. In NCC‐expressing HEK293 cells, mitochondrial dysfunction was induced to assess the effect on thiazide‐sensitive 22Na+ transport. 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. Importantly, affected members of six families with an MT‐TF variant additionally suffered from progressive chronic kidney disease. Maximal mitochondrial respiratory capacity was reduced in patient fibroblasts, caused by dysfunction of oxidative phosphorylation complex IV. In vitro pharmacological inhibition of complex IV, mimicking the effect of the mtDNA variants, demonstrated an inhibitory effect on NCC phosphorylation and NCC‐mediated sodium uptake. Pathogenic mtDNA variants in MT‐TF and MT‐TI can cause a Gitelman syndrome‐like syndrome. Genetic investigation of mtDNA should be considered in patients with unexplained Gitelman syndrome‐like tubulopathies.