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Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia

Groenestege, W. M. T., Thébault, S., van der Wijst, J., van den Berg, D., Janssen, R., Tejpar, S., van den Heuvel, L. P., van Cutsem, E., Hoenderop, J. G., Knoers, N. V. & Bindels, R. J., Aug-2007, In : The Journal of Clinical Investigation. 117, 8, p. 2260-2267 8 p.

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  • Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia

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DOI

  • Wouter M Tiel Groenestege
  • Stéphanie Thébault
  • Jenny van der Wijst
  • Dennis van den Berg
  • Rob Janssen
  • Sabine Tejpar
  • Lambertus P van den Heuvel
  • Eric van Cutsem
  • Joost G Hoenderop
  • Nine V Knoers
  • René J Bindels

Primary hypomagnesemia constitutes a rare heterogeneous group of disorders characterized by renal or intestinal magnesium (Mg(2+)) wasting resulting in generally shared symptoms of Mg(2+) depletion, such as tetany and generalized convulsions, and often including associated disturbances in calcium excretion. However, most of the genes involved in the physiology of Mg(2+) handling are unknown. Through the discovery of a mutation in the EGF gene in isolated autosomal recessive renal hypomagnesemia, we have, for what we believe is the first time, identified a magnesiotropic hormone crucial for total body Mg(2+) balance. The mutation leads to impaired basolateral sorting of pro-EGF. As a consequence, the renal EGFR is inadequately stimulated, resulting in insufficient activation of the epithelial Mg(2+) channel TRPM6 (transient receptor potential cation channel, subfamily M, member 6) and thereby Mg(2+) loss. Furthermore, we show that colorectal cancer patients treated with cetuximab, an antagonist of the EGFR, develop hypomagnesemia, emphasizing the significance of EGF in maintaining Mg(2+) balance.

Original languageEnglish
Pages (from-to)2260-2267
Number of pages8
JournalThe Journal of Clinical Investigation
Volume117
Issue number8
Publication statusPublished - Aug-2007
Externally publishedYes

    Keywords

  • Animals, Antibodies, Monoclonal/adverse effects, Antibodies, Monoclonal, Humanized, Antineoplastic Agents/adverse effects, Cetuximab, Colorectal Neoplasms/complications, Epidermal Growth Factor/genetics, ErbB Receptors/genetics, Female, Humans, Kidney/metabolism, Magnesium/metabolism, Male, Mutation, Pedigree, Protein Precursors/genetics, Protein Processing, Post-Translational/drug effects, Renal Tubular Transport, Inborn Errors/chemically induced, TRPM Cation Channels/biosynthesis, Tetany/chemically induced

ID: 92704454