Dominant isolated renal magnesium loss is caused by misrouting of the Na+,K+-ATPase gamma-subunit

Ann N Y Acad Sci. 2003 Apr:986:437-43. doi: 10.1111/j.1749-6632.2003.tb07226.x.

Abstract

Hereditary primary hypomagnesemia comprises a clinically and genetically heterogeneous group of disorders in which hypomagnesemia is due to either renal or intestinal Mg(2+) wasting. These disorders share the general symptoms of hypomagnesemia, tetany and epileptiformic convulsions, and often include secondary or associated disturbances in calcium excretion. In a large Dutch family with autosomal dominant renal hypomagnesemia, associated with hypocalciuria, we mapped the disease locus to a 5.6-cM region on chromosome 11q23. After candidate screening, we identified a heterozygous mutation in the FXYD2 gene, encoding the Na(+),K(+)-ATPase gamma-subunit, cosegregating with the patients of this family, which was not found in 132 control chromosomes. The mutation leads to a G41R substitution, introducing a charged amino acid residue in the predicted transmembrane region of the gamma-subunit protein. Expression studies in insect Sf9 and COS-1 cells showed that the mutant gamma-subunit protein was incorrectly routed and accumulated in perinuclear structures. In addition to disturbed routing of the G41R mutant, Western blot analysis of Xenopus oocytes expressing wild-type or mutant gamma-subunit showed mutant gamma-subunit lacking a posttranslational modification. Finally, we investigated two individuals lacking one copy of the FXYD2 gene and found their serum Mg(2+) levels to be within the normal range. We conclude that the arrest of mutant gamma-subunit in distinct intracellular structures is associated with aberrant posttranslational processing and that the G41R mutation causes dominant renal hypomagnesemia associated with hypocalciuria through a dominant negative mechanism.

Publication types

  • Review

MeSH terms

  • Animals
  • Calcium / metabolism
  • Homeostasis
  • Humans
  • Hypocalcemia / genetics
  • Kidney / enzymology
  • Kidney / metabolism*
  • Kinetics
  • Magnesium / metabolism*
  • Magnesium Deficiency / enzymology
  • Magnesium Deficiency / genetics
  • Sodium-Potassium-Exchanging ATPase / genetics*
  • Sodium-Potassium-Exchanging ATPase / metabolism*

Substances

  • FXYD2 protein, human
  • Sodium-Potassium-Exchanging ATPase
  • Magnesium
  • Calcium