Chapter 35 - Inherited Magnesium Disorders

Abstract

The molecular basis for a number of inherited disorders of magnesium homeostasis has been elucidated through discovery of genes encoding proteins critical to renal magnesium reabsorption in the thick ascending limb and distal convoluted tubule of the nephron. In the thick limb, mutations in claudins 16 and 19 impair paracellular cation transport and result in familial hypomagnesemia with hypocalcemia and nephrocalcinosis. In the distal convoluted tubule, a number of disorders impair active transcellular transport of magnesium. Mutation in the TRPM6 apical magnesium channel impairs gut absorption as well as renal reabsorption, and causes hypomagnesemia severe enough to alter parathyroid-regulated calcium metabolism, producing hypomagnesemia with secondary hypocalcemia. The potassium channels Kv1.1 and Kir4.1 are expressed in brain as well as distal renal tubule, and mutations not only cause renal magnesium wasting and hypomagnesemia but also neurologic impairment including ataxia. Hypomagnesemia also results from inherited defects in distal tubule basolateral membrane proteins EGF, the γ-subunit of the Na/K ATPase, and the calcium-sensing receptor, as well as the sodium chloride co-transporter mutated in Gitelman syndrome, each of which is important in the pathway for transcellular magnesium transport.