SUGP2基因及其突变在遗传性血色病中的致病作用及其机制研究

遗传性血色病诊断困难，如未早期干预，预后极差，基因检测有助于早诊早治，但我国血色病基因突变谱及热点突变仍不清楚。本项目前期通过外显子组测序发现我国血色病患者存在高频率的SUGP2 p.R639Q突变，提示其可能为潜在的热点突变，前期研究还发现，作为一种剪切因子，SUGP2有可能影响CIRBP的可变剪切从而影响铁代谢。本项目拟研究SUGP2及其突变与血色病的相关性及其机制。首先通过构建基因沉默、过表达及点突变等细胞模型，研究SUGP2基因及其突变对CIRBP可变剪切的作用以及CIRBP不同转录本对BMPER等铁代谢相关通路分子的影响，明确SUGP2基因及其突变影响铁代谢的机制；然后通过构建基因敲除及突变敲入小鼠模型，分析其是否通过以上通路影响小鼠铁代谢功能；最后通过临床样本的研究，分析SUGP2突变基因型与血色病表型的关系以及相关通路在其中的作用。研究对我国血色病的临床诊治具有重要意义。

The diagnosis of hereditary hemochromatosis (HH) in China has remained difficult leading to poor prognosis due to delay of the treatment. Genetic analysis would be helpful for the early diagnosis and treatment of HH. However, the mutation pattern and the hot spot mutation of HH in Chinese patients remain unclear. Our previous study has demonstrated a high frequency of SUGP2 p.R639Q, which may represent a potential hot spot mutation in Chinese patients with HH. Our previous study has also found that as a splicing factor, the SUGP2 may affect the alternative splicing and therefore the disturbance of iron metabolism. In the present study, the role of SUGP2 in the pathogenesis of HH, and the underlying mechanism will be explored by the construction of the gene silencing, over-expression and mutant cell model to analyze the effect of SUGP2 and SUGP2 p.R639Q on the alternative splicing of CIRBP transcripts and regulation of the different transcripts on the iron metabolism related molecular pathway genes such as BMPER, as well as the underlying mechanism. Then, through the construction of SUGP2 knock out and SUGP2 p.R639Q knock in mice, the effects of SUGP2 and SUGP2 p.R639Q on the iron metabolism, as well as the alterations of CIRBP transcripts and related genes will be demonstrated. Finally, through the analysis with clinical sample, the genotype-phenotype correlation of SUGP2 mutation, and the alterations of the corresponding pathway in the pathogenesis of HH will be explored. Taken together, the current study would be great helpful for the diagnosis and therapy of HH in China.