Resistance to hepcidin is conferred by hemochromatosis-associated mutations of ferroportin
Resistance to hepcidin is conferred by hemochromatosis-associated mutations of ferroportin
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DOI：
10.1182/blood-2005-02-0561
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发表时间：
2005-08-01
期刊：
影响因子：
20.3
通讯作者：
Townsend, ARM
中科院分区：
文献类型：
--
作者：
Drakesmith, H;Schimanski, LM;Townsend, ARM
铁转运蛋白（FPN）介导铁从细胞输出；FPN突变与铁超载疾病血色素沉着症有关。先前，我们发现A7713、V162del和G490D突变抑制FPN活性，但其他与疾病相关的FPN变体保留完全的铁输出能力。肽激素hepcidin抑制FPN作为稳态负反馈回路的一部分。我们在hepcidin存在下测量了野生型FPN和完全活性FPN突变体的表面表达和功能。我们发现FPN的Y64N和C326Y突变体对hepcidin抑制完全耐药，N144D和N144H部分耐药。因此，血色素沉着相关的FPN突变要么降低铁输出能力，要么产生对hepcidin不敏感的FPN变体。前一种突变类型与体内库普弗细胞铁沉积和正常的转铁蛋白饱和度有关，而后一种类型的FPN突变患者的转铁蛋白饱和度较高，并且倾向于在整个肝实质沉积铁。FPN相关血色素沉着病可能有不同的发病机制，这取决于致病的FPN突变。
Ferroportin (FPN) mediates iron export from cells; FPN mutations are associated with the iron overloading disorder hemochromatosis. Previously, we found that the A7713, V162del, and G490D mutations inhibited FPN activity, but that other disease-associated FPN variants retained full iron export capability. The peptide hormone hepcidin inhibits FPN as part of a homeostatic negative feedback loop. We measured surface expression and function of wild-type FPN and fully active FPN mutants in the presence of hepcidin. We found that the Y64N and C326Y mutants of FPN are completely resistant to hepcidin inhibition and that N144D and N144H are partially resistant. Hemochromatosis-associated FPN mutations, therefore, either reduce iron export ability or produce an FPN variant that is insensitive to hepcidin. The former mutation type is associated with Kupffer-cell iron deposition and normal transferrin saturation in vivo, whereas patients with the latter category of FPN mutation have high transferrin saturation and tend to deposit iron throughout the liver parenchyma. FPN-linked hemochromatosis may have a variable pathogenesis depending on the causative FPN mutant.