Inherited disorders of renal magnesium handling

The genetic basis and cellular defects of a number of primary magnesium was ting diseases have been elucidated over the past decade. This review correl ates the clinical pathophysiology with the primary defect and secondary cha nges in cellular electrolyte transport. The described disorders include (1) hypomagnesemia with secondary hypocalcemia, an early-onset, autosomal-rece ssive disease segregating with chromosome 9q12-22.2; (2) autosomal-dominant hypomagnesemia caused by isolated renal magnesium wasting, mapped to chrom osome 11q23; (3) hypomagnesemia with hypercalciuria and nephrocalcinosis, a recessive condition caused by a mutation of the claudin 16 gene (3q27) cod ing for a tight junctional protein that regulates paracellular Mg2+ transpo rt in the loop of Henle; (4) autosomal-dominant hypoparathyroidism, a varia bly hypomagnesemic disorder caused by inactivating mutations of the extrace llular Ca2+/Mg2+-sensing receptor, Casr gene, at 3q13.3-21 (a significant a ssociation between common polymorphisms of the Casr and extracellular Mg2concentration has been demonstrated in a healthy adult population); and (5) Gitelman syndrome, a recessive form of hypomagnesemia caused by mutations in the distal tubular NaCl cotransporter gene, SLC12A3, at 16q13. The basis for renal magnesium wasting in this disease is not known. These inherited conditions affect different nephron segments and different cell types and l ead to variable but increasingly distinguishable phenotypic presentations. No doubt, there are in the general population other disorders that have not yet been identified or characterized. The continued use of molecular techn iques to probe the constitutive and congenital disturbances of magnesium me tabolism will increase the understanding of cellular magnesium transport an d provide new insights into the way these diseases are diagnosed and manage d.