Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia.
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.
Department of Physiology, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Wouter M Tiel
WM
Groenestege
Stéphanie
S
Thébault
Jenny
J
van der Wijst
Dennis
D
van den Berg
Rob
R
Janssen
Sabine
S
Tejpar
Lambertus P
LP
van den Heuvel
Eric
E
van Cutsem
Joost G
JG
Hoenderop
Nine V
NV
Knoers
René J
RJ
Bindels
D000818:Animals; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use; D000068818:Cetuximab; D015179:Colorectal Neoplasms / Q000150:complications / Q000188:drug therapy; D004815:Epidermal Growth Factor / Q000235:genetics* / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D005260:Female; D006801:Humans; D007668:Kidney / Q000378:metabolism; D008274:Magnesium / Q000378:metabolism*; D008297:Male; D009154:Mutation; D010375:Pedigree; D011498:Protein Precursors / Q000235:genetics* / Q000378:metabolism*; D011499:Protein Processing, Post-Translational / Q000187:drug effects / Q000235:genetics*; D015499:Renal Tubular Transport, Inborn Errors / Q000139:chemically induced / Q000235:genetics* / Q000378:metabolism*; D050053:TRPM Cation Channels / Q000096:biosynthesis / Q000235:genetics; D013746:Tetany / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D011498:Protein Precursors; D050053:TRPM Cation Channels; C459082:TRPM6 protein, human; C042652:epidermal growth factor precursor; D004815:Epidermal Growth Factor; C512478:EGFR protein, human; D066246:ErbB Receptors; D008274:Magnesium; D000068818:Cetuximab