A TRPM7 variant shows altered sensitivity to magnesium that may contribute to the pathogenesis of two Guamanian neurodegenerative disorders
A TRPM7 variant shows altered sensitivity to magnesium that may contribute to the pathogenesis of two Guamanian neurodegenerative disorders
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DOI：
10.1073/pnas.0505149102
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发表时间：
2005-08-09
影响因子：
11.1
通讯作者：
Garruto, RM
中科院分区：
文献类型：
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作者：
Hermosura, MC;Nayakanti, H;Garruto, RM
在流行病学上，关岛肌萎缩侧索硬化症(ALS-G)和帕金森病痴呆(PD-G)与严重缺乏钙(Ca+)和镁(Mg2+)的环境有关。瞬时受体潜能Melastatin 7(TRPM7)是一种双功能蛋白，含有通道和激活区，参与细胞内钙离子、镁离子和微量金属离子浓度的动态平衡调节。有证据表明，TRPM7是结构性活跃的，可用通道的数量取决于细胞内游离镁离子的水平。我们在ALS-G和PD-G患者的子集中发现了一种TRPM7变体，它产生了一种带有错义突变的蛋白质T14821。重组T14821TRPM7显示出与WT TRPM7相同的激酶催化活性。然而，异源表达的T14821 TRPM7产生的功能通道对细胞内镁离子的抑制具有更高的敏感性。由于ALS-G和PD-G的发生与长期暴露在严重缺乏钙和镁的环境中有关，我们认为这种突变的TRPM7等位基因是这种环境中的易感基因。这项研究是解决这些疾病病因学中基因-环境相互作用这一重要问题的初步尝试。
Guamanian amyotrophic lateral sclerosis (ALS-G) and parkinsonism dementia (PD-G) have been epidemiologically linked to an environment severely deficient in calcium (Ca2+) and magnesium (Mg2+). Transient receptor potential melastatin 7 (TRPM7) is a bifunctional protein containing both channel and kinase domains that has been proposed to be involved in the homeostatic regulation of intracellular Ca2+, Mg2+, and trace metal ion concentration. There is evidence that TRPM7 is constitutively active and that the number of available channels is dependent on intracellular free Mg2+ levels. We found a TRPM7 variant in a subset of ALS-G and PD-G patients that produces a protein with a missense mutation, T14821. Recombinant T14821 TRPM7 exhibits the same kinase catalytic activity as WT TRPM7. However, heterologously expressed T14821 TRPM7 produces functional channels that show an increased sensitivity to inhibition by intracellular Mg2+. Because the incidence of ALS-G and PD-G has been associated with prolonged exposure to an environment severely deficient in Ca2+ and Mg2+, we propose that this variant TRPM7 allele confers a susceptibility genotype in such an environment. This study represents an initial attempt to address the important issue of gene-environment interactions in the etiology of these diseases.