Gitelman-Like Syndrome Caused by Pathogenic Variants in mtDNA.

吉特尔曼综合征 肾小管病变 线粒体DNA 生物 遗传学 低钙尿 低钾血症 巴特综合征 低镁血症 基因 突变 线粒体 粒线体疾病 医学
作者
Daan H H M Viering,Karl-Peter Schlingmann,Marguerite Hureaux,Tom Nijenhuis,Andrew Mallett,Melanie Chan,André P van Beek,Albertien M. van Eerde,Jean-Marie Coulibaly,Marion Vallet,Stéphane Decramer,Solenne Pelletier,Günter Klaus,Martin Kömhoff,Rolf Beetz,Chirag Patel,Mohan Shenoy,Eric J. Steenbergen,Glenn Anderson,Ernie M.H.F. Bongers,Carsten Bergmann,Daan M. Panneman,Richard J. Rodenburg,Robert Kleta,Pascal Houillier,Martin Konrad,Rosa Vargas-Poussou,Nine V A M Knoers,Detlef Bockenhauer,Jeroen H. F. de Baaij
出处
期刊:Journal of The American Society of Nephrology 被引量:1
标识
DOI:10.1681/asn.2021050596
摘要

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.
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