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

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Abstract

Primary hypomagnesemia constitutes a rare heterogeneous group of disorders characterized by renal or intestinal magnesium (Mg2+) wasting resulting in generally shared symptoms of Mg2+ 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 Mg2+ 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 Mg2+ 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 Mg2+ channel TRPM6 (transient receptor potential cation channel, subfamily M, member 6) and thereby Mg2+ 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 Mg2+ balance.

Authors

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