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O ur understanding of magnesium (Mg²⁺) regulation has recently been catapulted forward by the discovery of several disease loci for monogenic disorders of Mg²⁺ homeostasis. In this issue of the JCI, Groenestege et al. report that their study of a rare inherited Mg²⁺ wasting disorder in consanguineous kindred shows that EGF acts as an autocrine/paracrine magnesiotropic hormone (see the related article beginning on page 2260). EGF stimulates Mg²⁺ reabsorption in the renal distal convoluted tubule (DCT) via engagement of its receptor on the basolateral membrane of DCT cells and activation of the Mg²⁺ channel TRPM6 (transient receptor potential cation channel, subfamily M, member 6) in the apical membrane. These authors show that a point mutation in pro-EGF retains EGF secretion to the apical but not the basolateral membrane, disrupting this cascade and causing renal Mg²⁺ wasting. This work is another seminal example of the power of the study of monogenic disorders in the quest to understand human physiology.