Deficiency in the manganese efflux transporter SLC30A10 induces severe hypothyroidism in mice
Deficiency in the manganese efflux transporter SLC30A10 induces severe hypothyroidism in mice
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DOI：
10.1074/jbc.m117.783605
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发表时间：
2017-06-09
影响因子：
4.8
通讯作者：
Mukhopadhyay, Somshuvra
中科院分区：
文献类型：
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作者：
Hutchens, Steven;Liu, Chunyi;Mukhopadhyay, Somshuvra
锰是一种重要的金属，在升高的水平下变得有毒。SLC 30 A10是一种位于细胞表面的锰外排转运蛋白，其功能缺失突变可导致遗传性锰代谢紊乱，从而导致锰水平升高和帕金森样运动缺陷。潜在的疾病机制尚不清楚;因此，治疗具有挑战性。为了了解SLC 30 A10功能丧失在生物体水平上的后果，我们产生了Slc 30 a10基因敲除小鼠。在早期开发期间，敲除与对照无法区分。然而，令人惊讶的是，在断奶后，与对照组相比，基因敲除小鼠未能增加体重，体型较小，并且过早死亡（与6-8周龄相似）。在6周时，敲除小鼠的大脑、血液和肝脏中的锰水平比对照组高出20-60倍。出乎意料的是，组织学分析显示，敲除小鼠的大脑和肝脏基本上不受影响，但它们的甲状腺表现出广泛的变化。由于甲状腺功能减退会导致小鼠的生长缺陷和过早死亡，我们测定了甲状腺和垂体激素的变化。在6周时，与对照组相比，敲除组的甲状腺素水平显著降低（类似于50-80%），促甲状腺激素水平显著增加（类似于800-1000倍），表明Slc 30 a10敲除小鼠发生甲状腺功能减退症。重要的是，低锰饮食在敲除中产生较低的组织锰水平，并挽救了表型，表明锰毒性是根本原因。我们意料之外的发现强调了确定甲状腺功能障碍在锰诱导疾病的发生和进展中的作用的重要性，并将Slc 30 a10基因敲除小鼠确定为研究甲状腺生物学的新模型。
Manganese is an essential metal that becomes toxic at elevated levels. Loss-of-function mutations in SLC30A10, a cell-surface-localized manganese efflux transporter, cause a heritable manganese metabolism disorder resulting in elevated manganese levels and parkinsonian-like movement deficits. The underlying disease mechanisms are unclear; therefore, treatment is challenging. To understand the consequences of loss of SLC30A10 function at the organism level, we generated Slc30a10 knock-out mice. During early development, knock-outs were indistinguishable from controls. Surprisingly, however, after weaning and compared with controls, knock-out mice failed to gain weight, were smaller, and died prematurely (by similar to 6-8 weeks of age). At 6 weeks, manganese levels in the brain, blood, and liver of the knock-outs were similar to 20-60-fold higher than controls. Unexpectedly, histological analyses revealed that the brain and liver of the knock-outs were largely unaffected, but their thyroid exhibited extensive alterations. Because hypothyroidism leads to growth defects and premature death in mice, we assayed for changes in thyroid and pituitary hormones. At 6 weeks and compared with controls, the knock-outs had markedly reduced thyroxine levels (similar to 50-80%) and profoundly increased thyroid-stimulating hormone levels (similar to 800-1000-fold), indicating that Slc30a10 knock-out mice develop hypothyroidism. Importantly, a low-manganese diet produced lower tissue manganese levels in the knock-outs and rescued the phenotype, suggesting that manganese toxicity was the underlying cause. Our unanticipated discovery highlights the importance of determining the role of thyroid dysfunction in the onset and progression of manganese-induced disease and identifies Slc30a10 knock-out mice as a new model for studying thyroid biology.