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Genetic Heterogeneity in Familial Renal Magnesium Wasting

Burns and Allen Research Institute (V.K., J.S.A.) and Division of Endocrinology, Diabetes and Metabolism (V.K., J.S.A., J.E.G., R.K.R.), University of Southern California, School of Medicine, Los Angeles, California 90033; Division of Human Genetics (X.G., D.H.C.), Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, California 90048; and Corning Nichols Institute (M.R.P.), San Juan Capistrano, California 92690

Address all correspondence and requests for reprints to: Robert K. Rude, M.D., University of Southern California, 1975 Zonal Avenue, GN#6602, Los Angeles, California 90089-9317. E-mail: rrude60075{at}aol.com

Abstract

Isolated hereditary renal magnesium (Mg) wasting may result from mutations in the renal tubular epithelial cell tight junction protein paracellin-1 gene or the tubular Na(+),K(+)-ATPase -subunit gene FXYD2. The FXYD2 gene mutation was discovered in two Dutch families as an autosomal dominant disorder. It is characterized by isolated renal Mg wasting with resultant symptomatic hypomagnesemia. The defective FXYD2 gene in these families mapped to chromosome 11q23. Here, we describe an American family with a similar phenotype but without linkage to the 11q23 locus; in testing 22 individuals in the pedigree multipoint LOD scores for five different loci from the 11q23 region were equal to -2.97. Compared with unaffected family members and normal controls, affected family members harbored significant reductions in the serum and lymphocyte Mg concentrations and in the serum immunoreactive PTH level with a 4-fold increase in the mean fractional urinary Mg excretion rate during a normomagnesemic clamp. Bone mineral density at the lumbar spine and proximal femur was significantly reduced in affected family members. In conclusion, our data demonstrate locus heterogeneity for the phenotype of isolated renal Mg wasting with hypomagnesemia and suggest that hypomagnesemia, at least in this pedigree, may be associated with low bone mass.

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