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

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

Research output: Contribution to journalArticleAcademicpeer-review

255 Citations (Scopus)

Abstract

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
DOIs
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

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