Abstract
Our understanding of magnesium (Mg(2+)) regulation has recently been catapulted forward by the discovery of several disease loci for monogenic disorders of Mg(2+) homeostasis. In this issue of the JCI, Groenestege et al. report that their study of a rare inherited Mg(2+) wasting disorder in consanguineous kindred shows that EGF acts as an autocrine/paracrine magnesiotropic hormone (see the related article beginning on page 2260). EGF stimulates Mg(2+) reabsorption in the renal distal convoluted tubule (DCT) via engagement of its receptor on the basolateral membrane of DCT cells and activation of the Mg(2+) channel TRPM6 (transient receptor potential cation channel, subfamily M, member 6) in the apical membrane. These authors show that a point mutation in pro-EGF retains EGF secretion to the apical but not the basolateral membrane, disrupting this cascade and causing renal Mg(2+) wasting. This work is another seminal example of the power of the study of monogenic disorders in the quest to understand human physiology.
Publication types
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Research Support, N.I.H., Extramural
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Comment
MeSH terms
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Animals
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Antibodies, Monoclonal / adverse effects
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Antibodies, Monoclonal / therapeutic use
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Antibodies, Monoclonal, Humanized
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Antineoplastic Agents / adverse effects
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Antineoplastic Agents / therapeutic use
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Cetuximab
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Colorectal Neoplasms / complications
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Colorectal Neoplasms / drug therapy
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Epidermal Growth Factor / genetics*
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Epidermal Growth Factor / metabolism*
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ErbB Receptors / genetics
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ErbB Receptors / metabolism
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Female
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Humans
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Kidney / metabolism
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Magnesium / metabolism*
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Male
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Mutation*
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Pedigree
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Protein Precursors / genetics*
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Protein Precursors / metabolism*
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Protein Processing, Post-Translational / drug effects
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Protein Processing, Post-Translational / genetics*
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Renal Tubular Transport, Inborn Errors / chemically induced
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Renal Tubular Transport, Inborn Errors / genetics*
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Renal Tubular Transport, Inborn Errors / metabolism*
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TRPM Cation Channels / biosynthesis
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TRPM Cation Channels / genetics
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Tetany / chemically induced
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Tetany / genetics
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Tetany / metabolism
Substances
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Antibodies, Monoclonal
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Antibodies, Monoclonal, Humanized
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Antineoplastic Agents
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Protein Precursors
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TRPM Cation Channels
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TRPM6 protein, human
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epidermal growth factor precursor
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Epidermal Growth Factor
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EGFR protein, human
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ErbB Receptors
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Magnesium
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Cetuximab