Back to Search
Start Over
Dominant isolated renal magnesium loss is caused by misrouting of the Na+,K+-ATPase gamma-subunit
- Source :
- Annals of the New York Academy of Sciences, 986, pp. 437-43, Annals of the New York Academy of Sciences, 986, 437-43
- Publication Year :
- 2003
-
Abstract
- Item does not contain fulltext 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.
- Subjects :
- medicine.medical_specialty
Mutant
Locus (genetics)
Biology
Kidney
General Biochemistry, Genetics and Molecular Biology
Hypocalciuria
Hypomagnesemia
History and Philosophy of Science
Western blot
Internal medicine
medicine
Animals
Homeostasis
Humans
Magnesium
Na+/K+-ATPase
Gene
medicine.diagnostic_test
Hypocalcemia
General Neuroscience
Kidney metabolism
medicine.disease
Renal disorders [UMCN 5.4]
Kinetics
Endocrinology
Genetic defects of metabolism [UMCN 5.1]
Calcium
medicine.symptom
Sodium-Potassium-Exchanging ATPase
Cellular energy metabolism [UMCN 5.3]
Magnesium Deficiency
Subjects
Details
- ISSN :
- 00778923
- Volume :
- 986
- Database :
- OpenAIRE
- Journal :
- Annals of the New York Academy of Sciences
- Accession number :
- edsair.doi.dedup.....c65c4a909760c6b8e5b7cf31616cae1a