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Dominant Isolated Renal Magnesium Loss Is Caused by Misrouting of the Na + ,K + ‐ATPase γ‐Subunit
Author(s) -
MEIJ IWAN C.,
KOENDERINK JAN B.,
JONG JOKE C.,
PONT JAN JOEP H. H. M.,
MONNENS LEO A. H.,
HEUVEL LAMBERT P. W. J.,
KNOERS NINE V. A. M.
Publication year - 2003
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.2003.tb07226.x
Subject(s) - hypomagnesemia , mutant , hypocalciuria , microbiology and biotechnology , biology , protein subunit , mutation , chemistry , genetics , gene , magnesium , organic chemistry
A bstract : 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 γ‐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 γ‐subunit protein. Expression studies in insect Sf9 and COS‐1 cells showed that the mutant γ‐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 γ‐subunit showed mutant γ‐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 γ‐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.