Dominant isolated renal magnesium loss is caused by misrouting of the Na+,K+-ATPase gamma-subunit.
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.
Meij
Iwan C
IC
Department of Human Genetics, Institute of Cellular Signaling, University Medical Center Nijmegen, the Netherlands.
Koenderink
Jan B
JB
De Jong
Joke C
JC
De Pont
Jan Joep H H M
JJ
Monnens
Leo A H
LA
Van Den Heuvel
Lambert P W J
LP
Knoers
Nine V A M
NV
D000818:Animals; D002118:Calcium / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D006996:Hypocalcemia / Q000235:genetics; D007668:Kidney / Q000201:enzymology / Q000378:metabolism*; D007700:Kinetics; D008274:Magnesium / Q000378:metabolism*; D008275:Magnesium Deficiency / Q000201:enzymology / Q000235:genetics; D000254:Sodium-Potassium-Exchanging ATPase / Q000235:genetics* / Q000378:metabolism*
C416502:FXYD2 protein, human; D000254:Sodium-Potassium-Exchanging ATPase; D008274:Magnesium; D002118:Calcium