(854.8) Gitelman-like syndrome caused by pathogenic variants in mitochondrial DNA

Poster Board Number: E110

Jeroen de Baaij (Radboud University Medical Center), Daan Viering (Radboud University Medical Center), Karl Schlingmann (University of Münster), Marguerite Hureaux (Hôpital Européen Georges-Pompidou), Tom Nijenhuis (Radboud University Medical Center), Nine Knoers (University Medical Center Groningen), Rosa Vargas Poussou (Hôpital Européen Georges-Pompidou), Detlef Bockenhauer (University College London)

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, 156families 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.591Cgt;T (n=7), m.616Tgt;C (n=1), m.643Agt;G (n=1) (all in MT-TF) and m.4291Tgt;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.

Support or Funding Information

This work was financially supported by the IMAGEN project which is co-funded by the PPP Allowance made available by Health~Holland, Top Sector Life Sciences amp; Health, to stimulate public-private partnerships (IMplementation of Advancements in GENetic Kidney Disease, LSHM20009) and the Dutch Kidney Foundation (20OP+018). Additionally, we received support from ZonMW under the frame of EJPRD, the European Joint Programme on Rare Diseases (EJPRD2019-40). This project has received funding from the European Unions Horizon 2020 research and innovation programme under the EJP RD COFUND-EJP Namp;[deg] 825575 and the Netherlands Organization for Scientific Research (NWO Veni 016.186.012).

lt;agt;lt;/agt;lt;agt;This work was financially supported by the IMAGENlt;/agt; project which is co-funded by the PPP Allowance made available by Health~Holland, Top Sector Life Sciences amp;amp; Health, to stimulate public-private partnerships (IMplementation of Advancements in GENetic Kidney Disease, LSHM20009) and the Dutch Kidney Foundation (20OP+018). Additionally, we received support from ZonMW under the frame of EJPRD, the European Joint Programme on Rare Diseases (EJPRD2019-40). This project has received funding from the European Unions Horizon 2020 research and innovation programme under the EJP RD COFUND-EJP Namp;amp;[deg] 825575 and the Netherlands Organization for Scientific Research (NWO Veni 016.186.012).