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Inherited Disorders of Renal Magnesium Handling

Department of Laboratory Medicine & Pathobiology, University of Toronto, Toronto, Ontario, and Department of Medicine, University of British Columbia, Koerner Pavilion, University Hospital, Vancouver, British Columbia, Canada.

Correspondence to Dr. Gary A. Quamme, Department of Medicine, University Hospital, Koerner Pavilion, 2211 Wesbrook Mall, Vancouver, BC, Canada V6T 1Z3. Phone: 604-822-7156; Fax: 604-822-7897; E-mail: quamme{at}interchange.ubc.ca

Abstract. The genetic basis and cellular defects of a number of primary magnesium wasting diseases have been elucidated over the past decade. This review correlates the clinical pathophysiology with the primary defect and secondary changes in cellular electrolyte transport. The described disorders include (1) hypomagnesemia with secondary hypocalcemia, an earlyonset, autosomal-recessive disease segregating with chromosome 9q12-22.2; (2) autosomal-dominant hypomagnesemia caused by isolated renal magnesium wasting, mapped to chromosome 11q23; (3) hypomagnesemia with hypercalciuria and nephrocalcinosis, a recessive condition caused by a mutation of the claudin 16 gene (3q27) coding for a tight junctional protein that regulates paracellular Mg²⁺ transport in the loop of Henle; (4) autosomal-dominant hypoparathyroidism, a variably hypomagnesemic disorder caused by inactivating mutations of the extracellular Ca²⁺/Mg²⁺-sensing receptor, Casr gene, at 3q13.3-21 (a significant association between common polymorphisms of the Casr and extracellular Mg²⁺ concentration 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 lead 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 techniques to probe the constitutive and congenital disturbances of magnesium metabolism will increase the understanding of cellular magnesium transport and provide new insights into the way these diseases are diagnosed and managed.

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