活化的FX是体内凝血酶原唯一的生理性激活物，在共同凝血途径中起着关键作用。先天性FX基因缺陷性疾病发病率低，但危害严重。申请人前期在一个凝血功能异常的家系中，发现了两个未曾报道过可导致FX缺陷的突变。携带单突变位点表现为轻度凝血指标异常，而携带双突变的个体有严重的出血表现，由此推测，这两个新发现的突变可能存在协同效应，并可加重凝血异常。为此，本课题组拟：①依据F10基因同源性构建相应位点突变的小鼠模型，分析FX活性、表达量及凝血指标以及小鼠出血情况的变化，揭示突变对凝血功能的影响，并探讨两个突变的协同剂量效应。②通过观察细胞模型中新发现的F10突变与FX活性、稳定性及分泌的关系，揭示突变影响FX功能的分子机制。通过本研究，可明确新发现的F10突变位点与表型之间的关联，对凝血功能的影响及剂量效应，对于完善中国人群先天性FⅩ缺陷性疾病的遗传学特点及病理机制具有重要意义。

Activated FX is the only physiological activator of prothrombin in the body and plays a key role in the common coagulation pathway. The incidence of congenital F10 gene deficiency disease is low, but the symptom is serious. In the previous study, we found two novel mutations of F10 gene that caused abnormal coagulation in a pedigree. Patients carrying single mutation exhibited slightly abnormal coagulation, whereas ones with the two mutations had severe bleeding symptoms. Therefore, we speculated that the two novel mutations in the F10 gene may have a dose effect and aggravate coagulation abnormalities. Therefore, we proposed to: 1) construct a mouse model of corresponding site mutation based on the homology of F10 gene, and analyze the changes of FX activity, antigen, coagulation index and the phenotype of bleeding in mice to reveal the effects and synergistic effects of the two novel F10 gene mutations; 2) explore the effects of the two novel mutations on FX through observing the changes of FX activity, secretion and stability. The present project will clarify the effects of the two novel mutations on FX function and their synergistic effects on coagulation, which is of great significance for understanding the genetic characteristics and pathological mechanism of congenital FX-deficient disease in Chinese population.