Tmprss6 is a genetic modifier of the Hfe-hemochromatosis phenotype in mice
Tmprss6 is a genetic modifier of the Hfe-hemochromatosis phenotype in mice
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DOI：
10.1182/blood-2010-10-315507
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发表时间：
2011-04-28
期刊：
影响因子：
20.3
通讯作者：
Andrews, Nancy C.
中科院分区：
文献类型：
--
作者：
Finberg, Karin E.;Whittlesey, Rebecca L.;Andrews, Nancy C.
遗传性血色沉着症蛋白HFe促进海普西丁的表达，海普西丁是一种由肝脏产生的循环激素，它抑制饮食中铁的吸收和巨噬细胞铁的释放。HFE突变与肝骨形态发生蛋白(BMP)/SMAD信号通路受损有关。Tmprss 6是一种在铁缺乏性贫血中突变的跨膜型丝氨酸蛋白酶，它通过抑制BMP/SMAD信号通路来抑制海普西丁的表达。在目前的研究中，我们使用小鼠的遗传学方法来研究HFE和Tmprss 6在调节全身铁稳态中的关系。在HFE(-/-)小鼠中，Tmprss 6杂合缺失可降低全身铁负荷，而纯合子缺失会导致全身铁缺乏，肝脏中海普西丁和其他BMP/Smad靶基因的表达增加。相反，无论是HFE的遗传缺失还是肝脏HFE的过表达都不能调节Tmprss 6(-/-)小鼠的海普西丁升高和全身性铁缺乏。这些结果表明，Tmprss 6的遗传缺失以非HFE依赖的方式增加了BMP/Smad信号，从而可以恢复HFE(-/-)小鼠的BMP/Smad信号。此外，这些结果表明，人类同源基因TMPRSS6的自然遗传变异可能改变了HFE相关遗传性血色病的临床外显性，增加了药物抑制TMPRSS6可以减轻这种疾病中铁负荷的可能性。(血。2011；117(17)：4590-4599)
The hereditary hemochromatosis protein HFE promotes the expression of hepcidin, a circulating hormone produced by the liver that inhibits dietary iron absorption and macrophage iron release. HFE mutations are associated with impaired hepatic bone morphogenetic protein (BMP)/SMAD signaling for hepcidin production. TMPRSS6, a transmembrane serine protease mutated in iron-refractory iron deficiency anemia, inhibits hepcidin expression by dampening BMP/SMAD signaling. In the present study, we used genetic approaches in mice to examine the relationship between Hfe and Tmprss6 in the regulation of systemic iron homeostasis. Heterozygous loss of Tmprss6 in Hfe(-/-) mice reduced systemic iron overload, whereas homozygous loss caused systemic iron deficiency and elevated hepatic expression of hepcidin and other Bmp/Smad target genes. In contrast, neither genetic loss of Hfe nor hepatic Hfe overexpression modulated the hepcidin elevation and systemic iron deficiency of Tmprss6(-/-) mice. These results indicate that genetic loss of Tmprss6 increases Bmp/Smad signaling in an Hfe-independent manner that can restore Bmp/Smad signaling in Hfe(-/-) mice. Furthermore, these results suggest that natural genetic variation in the human ortholog TMPRSS6 might modify the clinical penetrance of HFE-associated hereditary hemochromatosis, raising the possibility that pharmacologic inhibition of TMPRSS6 could attenuate iron loading in this disorder. (Blood. 2011; 117(17): 4590-4599)