Hypomagnesemia with hypocalciuria

Magnesium wasting with hypocalciuria was first described by Geven et al. in 1987. In two presumably unrelated families, serum Mg2+ was found to be as low as 0.39 mmol/L without other plasma electrolyte abnormalities, including calcium (both serum and normal ionized), sodium, potassium, chloride and bicarbonate. Blood pH, renin activity and plasma aldosterone were in the normal range. The only abnormality found, in addition to hypomagnesemia, was lowered renal excretion of calcium. Family members of the probands had low serum Mg2+ also, but lacked clinical symptoms of Mg2+ depletion. Retention values of orally administered isotope 28 of Mg and the effects of Mg2+ infusion on renal reabsorption showed that the defect must be located in the kidney. In these two families the disorder was inherited as an autosomal dominant trait. The disease locus was designated HOMG2 (hypomagnesemia 2), it is located on chromosome 11q23. Within the linkage region, the FXYD2gene, encoding the sodiumpotassium-ATPase gamma-subunit was found. The Na+,K+-ATPase provides the driving force for active transport processes in the kidney, and is responsible for the maintenance of the transmembrane potential and the Na+-gradient which drive passive reabsorption and facilitated Na+-coupled transport. Mutation analysis of FXYD2 revealed a single heterozygous mutation in the patients of both families resulting in the substitution of a highly conserved hydrophobic Glycine residue within the putative transmembrane region with a hydrophilic Arginine residue. Transient expression studies have shown that this amino acid substitution results in bad processing and incorrect localization of the sodium-potassium-ATPase gamma-