A Heterozygous de novo Mutation in SLC41A1 Causes Hypomagnesemia and Renal Magnesium Wasting
Authors: de Baaij Jeroen H.F. , Arjona Francisco J. , Schlingmann Karl P. , Burtey Stéphane , Thomassen Michael , van der Wijst Jenny , Knoers Nine V.A.M. , Bindels René J.M. , Konrad Martin , Hoenderop Joost G.J. 
Published: November 2023

Over the last decades, the identification of hereditary hypomagnesemia‐causing genes has increased our understanding of the mechanisms underlying renal magnesium (Mg2+) reabsorption. In the kidney, urinary Mg2+ excretion is determined in the distal convoluted tubule, as no Mg2+ is reabsorbed beyond this segment. In the distal convoluted tubule, the epithelial Mg2+ channel transient receptor potential melastatin type 6 (TRPM6) mediates active Mg2+ reabsorption from the pro‐urine into the cell. However, to date the molecular identity of the proteins facilitating Mg2+ extrusion from the cell towards the blood remains elusive.In this study, a three‐year‐old girl was identified with tetanic convulsions caused by severe hypomagnesemia and hypocalcemia. A Mg2+‐loading test showed urinary Mg2+ wasting, demonstrating a renal origin of the disease. The aim of this study was to identify the gene mutation that is causative for hypomagnesemia in this patient. Moreover, we investigated the molecular mechanism of disease by cellular Mg2+ transport experiments and by gene expression knockdown experiments in the zebrafish model.Whole exome sequencing identified a heterozygous de novo p.Ile98Phe mutation in the SLC41A1 gene. 25Mg2+ transport assays in human embryonic kidney 293 cells overexpressing SLC41A1 demonstrated that this transporter mediates cellular Mg2+ extrusion. To examine the pathogenicity of the mutation, a slc41a1 zebrafish knockdown model was generated using two separate morpholino approaches. Slc41a1 knockdown resulted in a 20% reduction of the total magnesium content. Overexpression of SLC41A1 in slc41a1‐knockdown zebrafish restored the total magnesium content. Conversely, total magnesium levels were not normalized in slc41a1‐knockdown zebrafish overexpressing the patient's SLC41A1 mutant. Co‐expression of wild‐type and mutant SLC41A1 in zebrafish disturbed the Mg2+ balance, demonstrating that mutant SLC41A1 has a dominant negative effect over wild‐type SLC41A1.In conclusion, a heterozygous de novo mutation in SLC41A1 causes hypomagnesemia and renal Mg2+ wasting. These findings demonstrate the essential role of SLC41A1 in renal Mg2+ handling and maintenance of body Mg2+ balance. Based on our experiments, we propose that SLC41A1 may facilitate basolateral Mg2+ extrusion in the distal convoluted tubule.Support or Funding InformationThis work was supported by the Long‐Term Fellowship from the European Renal Association ‐ European Dialysis and Transplant Association (ERA‐EDTA, ERA LTF 175‐2014) and the Impulsion Grant from the ERA‐EDTA Working Group on Inherited Kidney Disorders (WGIKD) to dr. Francisco J. Arjona; and by the grants from the Netherlands Organization for Scientific Research (NWO VICI 016.130.668) and the EURenOmics project from the European Union seventh Framework Programme (FP7/2007–2013, agreement no. 305608) to prof. dr. Joost G.J. Hoenderop. Dr. Jeroen H.F. de Baaij is supported by grants from NWO (Rubicon 825.14.021), the Dutch Kidney Foundation (Kolff 14OKG17) and RIMLS.