Hypomagnesemia 2, Renal

A number sign (#) is used with this entry because of evidence that renal hypomagnesemia-2 (HOMG2) is caused by heterozygous mutation in the FXYD2 gene (601814) on chromosome 11q23.

For a discussion of genetic heterogeneity of renal hypomagnesemia, see 602014.

Clinical Features

Geven et al. (1987) reported 2 unrelated families in which hypomagnesemia due to renal magnesium loss was inherited as an autosomal dominant trait. Magnesium infusions performed in 2 patients showed not only a reduced renal magnesium threshold but also a lowered renal tubular maximum for magnesium. All hypomagnesemic members of the family also had a lowered urinary excretion of calcium, presumably as a consequence of increased reabsorption in the loop of Henle. Male-to-male transmission was observed in both families.

De Baaij et al. (2015) studied 2 families segregating autosomal dominant isolated hypomagnesemia. In the first family, hypokalemia and hypomagnesemia were discovered in a 34-year-old Dutch man who presented with pulmonary embolism. He reported a long history of muscle cramps and fatigue, as well as increased fluid intake. His deceased parents had shown no relevant symptoms apart from increased fluid intake in his father. His 9-year-old daughter and 7-year-old son were examined because of muscle cramps, and were found to have hypomagnesemia with hypermagnesuria and hypocalciuria. Both children had a normal growth pattern, normal blood pressure, no dysmorphic features, and unremarkable renal ultrasound and hand x-ray. In the second family, the proband was a 67-year-old Belgian man in whom hypomagnesemia and hypokalemia were found during an episode of tetanic cramps at age 44 years. Examination revealed hypertension, chondrocalcinosis, and renal failure, with hypomagnesemia, hypermagnesuria, and hypocalciuria. His mother was also affected, with chronic fatigue and joint problems for which she took Mg(2+) supplements. The proband's 41-year-old daughter was diagnosed in young adulthood with hypomagnesemia and hypokalemia, and her 16-year-old daughter, who had 2 episodes of seizures, was also found to be affected. Both the daughter and granddaughter had normal renal function apart from hypermagnesuria and hypocalciuria. Symptoms in affected family members included chronic fatigue, generalized weakness, dysesthesias of the face and hands, and frequent cramps of the lower extremities.

Mapping

In the 2 Dutch families described by Geven et al. (1987), Meij et al. (1999) performed a genomewide linkage study. They excluded a possible candidate region on chromosome 9q that encompassed the gene for intestinal hypomagnesemia with secondary hypocalcemia (602014), which maps to 9q12. They then demonstrated linkage to a marker on 11q23 (maximum lod = 6.41 at theta = 0). Detailed haplotype analyses identified a common haplotype segregating in the 2 families, suggesting both their relationship through a common ancestor and the existence of a single, hypomagnesemia-causing mutation in the families.

Heterogeneity

Kantorovich et al. (2002) reported an American family with renal hypomagnesemia without linkage to the 11q23 locus. In testing 22 individuals in the pedigree, multipoint lod scores for 5 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 parathyroid hormone (PTH; 168450) level with a 4-fold increase in the mean fractional urinary Mg excretion rate during a normomagnesemic clamp. The authors concluded that their 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.

Meij et al. (2003) analyzed the FXYD2, CLDN16 (603959), and SLC12A3 (600968) genes in a father and daughter with renal hypomagnesemia and hypocalciuria, but found no mutations. The authors concluded that at least 1 additional gene must be involved in renal magnesium handling.

Molecular Genetics

Meij et al. (2000) screened the FXYD2 gene in affected members of a large Dutch kindred with autosomal dominant hypomagnesemia originally described by Geven et al. (1987) and identified a putative dominant-negative heterozygous mutation (G41R; 601814.0001) that cosegregated with the disorder in 3 different branches of the family and was absent from 132 control chromosomes. The mutation occurred within the putative transmembrane domain of the protein. The authors investigated 2 individuals with an 11q23.3-qter deletion including FXYD2. Both had normal serum magnesium ion levels, showing that rather than haploinsufficiency, the presence of mutant gamma subunit causes hypomagnesemia, consistent with a dominant-negative mechanism. Studies in insect cells showed that whereas the wildtype gamma subunit localized predominantly to the plasma membrane, the mutant protein accumulated in the cytoplasm. A routing defect in transfected COS-1 cells was also observed. This was said to have been the first example of mutations in a gene encoding an Na+,K(+)-ATPase gamma subunit to be implicated in human disease.

In affected members of a Dutch family and a Belgian family segregating autosomal dominant isolated hypomagnesemia, who were negative for mutation in the SLC12A3, HNF1B (189907), and CLCNKB (602023) genes, de Baaij et al. (2015) identified heterozygosity for the G41R mutation in the FXYD2 gene. Patients from both families as well as the Dutch kindred originally reported by Geven et al. (1987) shared the same haplotype, suggesting that all 3 families are related through a common ancestor.