Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia
Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypomagnesemia
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DOI：
10.1172/jci31680
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发表时间：
2007-08-01
影响因子：
15.9
通讯作者：
Bindels, Rene J.
中科院分区：
文献类型：
--
作者：
Groenestege, Wouter M. Tiel;Thebault, Stephanie;Bindels, Rene J.
原发性低镁血症是一组罕见的异质性疾病，其特征为肾或肠镁（Mg 2+）消耗，导致普遍共有的Mg 2+耗竭症状，如手足抽搐和全身性惊厥，通常包括钙排泄相关紊乱。然而，大多数参与Mg 2+处理生理学的基因是未知的。通过在孤立的常染色体隐性遗传性肾性低镁血症中发现EGF基因突变，我们首次确定了一种对全身Mg 2+平衡至关重要的促镁激素。该突变导致pro-EGF的基底外侧分选受损。因此，肾EGFR被不充分地刺激，导致上皮Mg 2+通道TRPM 6（瞬时受体电位阳离子通道，亚家族M，成员6）的不充分活化，从而导致Mg 2+损失。此外，我们发现，西妥昔单抗，EGFR的拮抗剂，治疗结直肠癌患者，发展低镁血症，强调EGF在维持Mg 2+平衡的意义。
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.