Gitelman-Like Syndrome Caused by Pathogenic Variants in mtDNA
| Autor: | Martin Konrad, Rolf Beetz, Marguerite Hureaux, Rosa Vargas-Poussou, Robert Kleta, Günter Klaus, Tom Nijenhuis, Ernie M.H.F. Bongers, Daan M. Panneman, Solenne Pelletier, Richard J. Rodenburg, Martin Kömhoff, André P van Beek, Pascal Houillier, Jean-Marie Coulibaly, Nine V A M Knoers, Marion Vallet, Stéphane Decramer, Melanie Chan, Glenn Anderson, Carsten Bergmann, Detlef Bockenhauer, Mohan Shenoy, Jeroen H. F. de Baaij, Eric J. Steenbergen, Chirag Patel, Albertien M. van Eerde, Karl-Peter Schlingmann, Daan H H M Viering, Andrew Mallett |
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| Přispěvatelé: | Center for Liver, Digestive and Metabolic Diseases (CLDM) |
| Jazyk: | angličtina |
| Rok vydání: | 2022 |
| Předmět: |
Male
Kidney DISEASE ion transport Genotype Solute Carrier Family 12 Member 3 Gitelman-s syndrome CHANNEL GENE Child RNA Transfer Ile PHOSPHORYLATION NCC biology genetic renal disease blood pressure Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6] General Medicine Middle Aged chronic kidney failure TUBULE Na transport Pedigree mitochondria BARTTER-SYNDROME Phenotype medicine.anatomical_structure Mitochondrial respiratory chain MAGNESIUM Nephrology Child Preschool epithelial sodium transport Female Gitelman Syndrome Adult Mitochondrial DNA Adolescent human genetics KCNJ10 DNA Mitochondrial Models Biological Polymorphism Single Nucleotide RNA Transfer Phe Young Adult Tubulopathy medicine Humans Distal convoluted tubule HYPOMAGNESEMIA Aged CLCNKB Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7] MITOCHONDRIAL-DNA MUTATION Base Sequence Infant Gitelman syndrome medicine.disease Molecular biology SODIUM-CHLORIDE COTRANSPORTER HEK293 Cells Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11] Basic Research Mutation biology.protein Nucleic Acid Conformation chronic kidney disease |
| Zdroj: | J Am Soc Nephrol Journal of the American Society of Nephrology, 33(2), 305-325. AMER SOC NEPHROLOGY Journal of the American Society of Nephrology, 33, 305-325 Journal of the American Society of Nephrology, 33, 2, pp. 305-325 |
| ISSN: | 1046-6673 |
| Popis: | Contains fulltext : 248375.pdf (Publisher’s version ) (Closed access) 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 (22)Na(+) 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. |
| Databáze: | OpenAIRE |
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