Gitelman-Like Syndrome Caused by Pathogenic Variants in mtDNA.

Area of Science:

• Genetics
• Molecular Biology
• Nephrology

Background:

• Gitelman syndrome is a common hereditary salt-losing tubulopathy causing hypokalemic alkalosis and hypomagnesemia.
• It is primarily caused by pathogenic variants in SLC12A3, encoding the renal distal convoluted tubule Na+-Cl- cotransporter (NCC).
• However, ~10% of patients with Gitelman syndrome phenotype have an unknown genotype.

Purpose of the Study:

• To investigate mitochondrial DNA (mtDNA) variants as a potential cause of Gitelman-like electrolyte abnormalities.
• To assess the impact of identified mtDNA variants on mitochondrial function and NCC activity.

Main Methods:

• Identified mtDNA variants in families with Gitelman-like electrolyte abnormalities.
• Investigated variants in MT-TI and MT-TF genes.
• Assessed mitochondrial respiratory chain function in patient fibroblasts.
• Induced mitochondrial dysfunction in NCC-expressing cells to study thiazide-sensitive sodium transport.

Main Results:

• Four pathogenic mtDNA variants (m.591C>T, m.616T>C, m.643A>G in MT-TF, and m.4291T>C in MT-TI) were found in 13 families.
• Affected individuals with MT-TF variants developed progressive chronic kidney disease.
• Patient fibroblasts showed impaired oxidative phosphorylation complex IV and reduced mitochondrial respiratory capacity.
• In vitro studies demonstrated that complex IV inhibition reduced NCC phosphorylation and sodium uptake.

Conclusions:

• Pathogenic mtDNA variants in MT-TF and MT-TI are a cause of Gitelman-like syndrome.
• mtDNA genetic investigation should be considered for unexplained Gitelman syndrome-like tubulopathies.