Department of Clinical and Biological Science, University of Torino, Turin, Italy.
Blood. 2010 Apr 22;115(16):3382-9. doi: 10.1182/blood-2009-09-240960. Epub 2010 Feb 23.
Transferrin receptor 2 (TFR2) is a transmembrane protein that is mutated in hemochromatosis type 3. The TFR2 gene is transcribed in 2 main isoforms: the full-length (alpha) and a shorter form (beta). alpha-Tfr2 is the sensor of diferric transferrin, implicated in the modulation of hepcidin, the main regulator of iron homeostasis. The function of the putative beta-Tfr2 protein is unknown. We have developed a new mouse model (KI) lacking beta-Tfr2 compared with Tfr2 knockout mice (KO). Adult Tfr2 KO mice show liver iron overload and inadequate hepcidin levels relative to body iron stores, even though they increase Bmp6 production. KI mice have normal transferrin saturation, liver iron concentration, hepcidin and Bmp6 levels but show a transient anemia at young age and severe spleen iron accumulation in adult animals. Fpn1 is strikingly decreased in the spleen of these animals. These findings and the expression of beta-Tfr2 in wild-type mice spleen suggest a role for beta-Tfr2 in Fpn1 transcriptional control. Selective inactivation of liver alpha-Tfr2 in KI mice (LCKO-KI) returned the phenotype to liver iron overload. Our results strengthen the function of hepatic alpha-Tfr2 in hepcidin activation, suggest a role for extrahepatic Tfr2 and indicate that beta-Tfr2 may specifically control spleen iron efflux.
转铁蛋白受体 2（TFR2）是一种跨膜蛋白，在血色病 3 型中发生突变。TFR2 基因转录为 2 种主要的异构体：全长（α）和较短形式（β）。α-Tfr2 是二价转铁蛋白的传感器，参与铁调素的调节，铁稳态的主要调节剂。β-Tfr2 蛋白的功能未知。我们开发了一种新的小鼠模型（KI），与 Tfr2 敲除小鼠（KO）相比，缺乏β-Tfr2。成年 Tfr2 KO 小鼠表现出肝脏铁过载和铁调素水平不足，相对于体内铁储存量，尽管它们增加了 Bmp6 的产生。KI 小鼠的转铁蛋白饱和度、肝脏铁浓度、铁调素和 Bmp6 水平正常，但在幼年时出现短暂性贫血，成年动物的脾脏铁积累严重。这些动物的 Fpn1 明显减少。这些发现以及β-Tfr2 在野生型小鼠脾脏中的表达表明β-Tfr2在 Fpn1 转录控制中起作用。在 KI 小鼠中选择性失活肝脏α-Tfr2（LCKO-KI）使肝脏铁过载的表型恢复正常。我们的结果加强了肝α-Tfr2 在铁调素激活中的作用，提示了肝外 Tfr2 的作用，并表明β-Tfr2 可能特异性控制脾脏铁的流出。
