TFR2 R25C突变体影响铁代谢的分子机制研究

Hereditary hemochromatosis (HH) is a common iron overload disorder in the worldwide scale, which seriously endanger human health and survival. HFE gene mutation is the most common type of HH, but our previous studies have found that non-HFE gene mutations are the main type in Chinese HH patients and a third of the patients carry mutations in transferrin receptor 2 (TFR2) gene. Among them, Arg25Cys (R25C, a cysteine instead of an arginine at position 25) in TFR2 gene is a novel mutation, which has not been reported at home and abroad. Lower serum hepcidin level of the patient indicated that R25C has influence to the iron metabolism, but the molecular mechanism is unclear. In this project, we will use cell models to investigate the molecular pathological mechanism of TFR2 R25C in iron metabolism through three aspects by conventional biochemistry and molecular biology techniques. These aspects include the signal transduction pathways, the protein stability of TFR2 R25C and the recycling ability of TFR2 with R25C mutation. Elucidate the pathogenic mechanism of R25C, will be helpful to understand the regulatory effect of TFR2 gene on iron homeostasis and provide an important basis for its future application in the clinical diagnosis and treatment. Most importantly, we hope to promote domestic study of hereditary hemochromatosis through this project.

遗传性血色病（hereditary hemochromatosis，HH）是一种全球常见的铁过载性疾病，严重危害人类的健康和生存。HFE基因突变是HH最常见的类型，但课题组发现，我国HH患者以非HFE基因突变为主，其中1/3的患者带有转铁蛋白受体2（TFR2）基因突变。这些突变中，TFR2 Arg25Cys（R25C，半胱氨酸C取代第25位精氨酸R）是一个新的点突变，国内外文献均未见报道。患者血清铁调素hepcidin降低，表明R25C对铁代谢可能有影响，但分子机制不清楚。因此，本项目拟在体外，应用分子生物学相关技术，从“铁代谢信号转导通路”、“TFR2蛋白稳定性”及“受体再循环”三方面，探讨R25C影响铁代谢的分子机制。阐明R25C致病机理，有助于深入理解TFR2基因对铁稳态的调节作用，并为其今后在临床诊断和治疗方面的应用提供重要依据。更重要的是，希望通过本项目推动国内血色病研究。

遗传性血色病（hereditary hemochromatosis，HH）是一种全球常见的铁过载性疾病，严重危害人类的健康和生存。HFE基因突变是HH最常见的类型，但课题组发现，我国HH患者以非HFE基因突变为主，其中1/3的患者带有转铁蛋白受体2（TFR2）基因突变。这些突变中，TFR2 Arg25Cys（R25C，半胱氨酸C取代第25位精氨酸R）是一个新的点突变，国内外文献均未见报道。患者血清铁调素hepcidin降低，表明R25C突变对铁代谢可能有影响，但分子机制不清楚。因此，本项研究通过构建TFR2野生型和R25C突变型稳转细胞株，从“铁代谢信号转导通路”、“TFR2蛋白稳定性”及“受体再循环”三方面，探讨R25C影响铁代谢的分子机制。我们发现R25C突变通过下调BMP/SMAD 和MAPK/ERK1/2 信号通路中的pSMAD1/5/9和pERK1/2 蛋白抑制HAMP基因的表达，从而使细胞内的铁含量增加。R25C突变不影响载铁转铁蛋白Holo-Tf与TFR2的结合和内吞，同时也不影响Holo-Tf对TFR2蛋白的稳定作用。虽然R25C突变也不影响TFR2蛋白二聚体的稳定性，但该突变通过降低TFR2在溶酶体中的降解，延长TFR2蛋白的半衰期。阐明R25C致病机理，有助于深入理解TFR2基因对铁稳态的调节作用，并为其今后在临床诊断和治疗方面的应用提供重要依据。更重要的是，希望通过本项目推动国内血色病研究。

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