先天性凝血因子Ⅻ缺陷症的临床表型及基因分析

科研成果详情

题名	先天性凝血因子Ⅻ缺陷症的临床表型及基因分析
其他题名	Phenotype and gene analysis of congenital coagulation FⅫ deficiency
作者	李姗姗
学位类型	硕士
导师	江明华
答辩日期	2020-05-31
学位授予单位	温州医科大学
学位专业	医学检验
关键词	凝血因子Ⅻ 基因突变蛋白结构保守性分析
摘要	研究背景：凝血因子Ⅻ（Coagulation Factor Ⅻ, FⅫ）是由肝细胞合成的糖蛋白，以单链形式分泌入血浆，其基因位于5q33-qter，包括13个内含子和14个外显子。成熟酶原型FⅫ由596个氨基酸残基组成，包括重链和轻链。FⅫ缺陷的患者因缺乏明显的临床症状，多数发病隐匿。同时，遗传性凝血因子Ⅻ缺陷症是一种罕见的常染色体隐性遗传病，因此全球发现的基因突变甚少。加之，目前暂无FⅫ活性形式晶体结构的报道，该蛋白结构和功能并无完整的定论。因此，需要更多的实验研究帮助我们认识遗传性凝血因子Ⅻ缺陷症。目的： 1. 通过分析FⅫ缺陷症患者的F12基因序列，研究其致病的遗传因素； 2. 通过MegAlign等软件分析突变氨基酸位点的保守性，推测该位点与FⅫ结构和功能的亲密度，同时运用PYMOL软件预测突变型FⅫ与野生型FⅫ蛋白结构差异。方法： 1. 表型分析筛选FⅫ缺陷症患者：回顾性分析筛选出APTT明显延长及PT、FIB、TT基本正常且APTT纠正实验可被纠正的标本，进一步检测凝血因子Ⅷ、Ⅸ、Ⅺ、Ⅻ促凝活性（FⅧ∶C、FⅨ∶C、FⅪ∶C、FⅫ∶C）。上述项目由法国STAGO全自动血凝仪完成检测，筛选出FⅫ∶C明显降低的患者。采用ASSAYPRO公司提供的ELISA试剂盒检测FⅫ抗原（FⅫ∶Ag）。 2. 凝血因子Ⅻ缺陷症患者的基因分析：提取凝血因子Ⅻ缺陷症患者的基因组，用primer5.0TM软件设计7对引物，覆盖F12基因的所有外显子，部分内含子及侧翼序列，PCR扩增，电泳鉴定扩增产物，提纯，测定其核苷酸序列，BLAST分析序列结果，寻找突变位点。 3. 突变氨基酸的保守性分析及突变蛋白结构预测分析：若2.中发现错义突变，使用MegAlign软件分析人类与其他哺乳动物（家鼠、野猪、北极熊、苏门答腊猩猩、野骆驼）在该错义突变氨基酸位点的保守性。用PYMOL软件模拟分析突变蛋白与野生型FⅫ的结构差异。结果： 1. 本研究筛选出4位FⅫ缺陷症患者，他们均存在APTT的明显延长，以及FⅫ∶C和FⅫ∶Ag的明显降低； 2. 成功在4位FⅫ缺陷症患者的F12基因中找到了6种基因突变，包括2种错义突变，1种短片段缺失，1种无义突变，2种剪接位点突变，它们是p.Pro163Leu、p.Cys540Arg、g.8810_8814delGTCTA、p.Ser460Ter、IVS6–1G＞A和IVS13–1 G＞A，其中前5种为未报道的突变； 3. 用MegAlign软件对2.发现的两种错义突变对应的氨基酸位点进行保守性分析，结果为高度保守，同时用PYMOL软件模拟构建突变蛋白和野生型FⅫ的蛋白结构，发现除突变位点外，蛋白其他位置的结构也发生了改变。结论： 1. 四位患者的F12基因突变包括纯合突变和杂合突变，这些基因改变是导致其凝血因子Ⅻ缺陷的遗传因素，且这些基因突变不仅影响了FⅫ的活性，同时其抗原水平也明显下降； 2. 本研究中发现的2种错义突变位点在不同物种间的保守性较高，说明这些位点与FⅫ的结构和功能密切相关。用PYMOL软件模拟蛋白构象，突变FⅫ相较野生型FⅫ，其蛋白结构多处发生改变，可能影响了相应区域的功能，而引起血浆FⅫ∶C和FⅫ∶Ag水平同时降低； 3. 在人类突变基因数据库中记录的F12基因的突变仅四十余种，本研究中发现了5例未报道的突变基因，为今后对遗传性凝血因子Ⅻ缺陷症发病机制的研究及诊断方法的建立提供了良好的实验基础。
其他摘要	Background Coagulation FⅫ(Coagulation Factor Ⅻ, FⅫ) is a glycoprotein which produced by liver cells, and circulates in plasma as a single-chain. F12 is located in the 5q33-qter, including 14 exons and 13 introns. Mature FⅫ is composed of 596 amino acid, including heavy and light chain. Most of coagulation FⅫ deficiency were difficult to be perceived, because of the lack of obvious clinical symptoms. At the same time, the crystal structure of activated FⅫ analysis is vacant. So coagulation FⅫ deficiency is a rare and recessive autosomal hereditary disease, which reported rarely in global, let alone pathogenesis and the influence to the body by the disease. So coagulation FⅫ deficiency needs more and more experimental research. Objectives 1. Analyse the genetic pathogenesis of coagulation FⅫ deficiency by the analysis of F12 gene sequence. 2. Analyze the conservative of the mutation sites which may relate to the structure and function of FⅫ by MegAlign. Predict the protein structure change between mutation protein and Wild-type protein by PYMOL software. Methods 1. Screening FⅫ deficiency by phenotypic analysis: plasma prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen (FIB), thrombin time (TT) and blood coagulation factor Ⅷ, Ⅸ, Ⅺ, Ⅻ activity (FⅧ: C, FⅨ: C, FⅪ:C, FⅫ: C) were detected by STAGO coagulation analyzer, while enzyme linked immunosorbent assay (ELISA) was used to detect the antigen of FⅫ. Firstly, we screened specimens with significantly prolonged APTT, normal PT, FIB, TT and correctable APTT mixing study. Secondly, we detected the coagulation factor activity of the screened specimens. Finally, we detected the antigen of FⅫ of specimens which FⅫ: C reduced significantly. 2. Gene analysis of FⅫ deficiency: The genomes of screened specimens were extracted. And the seven couple primers which covered all exons of F12 gene, part of introns and flanking sequence were designed by primer5.0TM software. And the target sequences were got by PCR amplification, electrophoresis method and purification. Then sequenced. Mutations were analyzed by BLAST. 3. Conservative analysis and protein structural prediction: The conservative of the missense mutation sites which found in step 2 were analyzed by MegAlign software between humans and other mammals, such as mice, wild boar, polar bear, sumatran orangutan and wild camel. The structural changes between mutation protein and wild-type protein were predicted by PYMOL software. Results 1. Prolonged APTT were found in four FⅫ deficiency cases whose FⅫ:C and FⅫ:Ag reduced significantly. 2. Six mutations were found in the four cases, including two missense mutation, one short pieces missing, one nonsense mutation and two splice site mutations. They are p.Pro163Leu, p.Cys540Arg, g.8810_8814delGTCTA, p.Ser460Ter, IVS6–1G＞A and IVS13–1 G＞A. The first five were novel. 3. The conservative of the two missense mutations found in step 2 was analyzed by MegAlign software. And the results showed they are highly conservative. Meanwhile, PYMOL software was used to predict the protein structure of mutant and wild-type FⅫ. And the result suggested that there were many structural changes which were not limited to the mutant sites. Conclusion 1. Homozygous mutation and heterozygous mutation occurred in four cases, which lead the FⅫ deficiency. As the results of clinical phenotype showed, the change of F12 also affect the level of activity and antigen of FⅫ. 2. It was high conservative in the 2 missense mutation among different species. It would be a strong evidence for the closely relation between these sites and the function of FⅫ. As PYMOL software predicted, many structural differences occured between mutant FⅫ and wild-type FⅫ, which might affect the function of FⅫ and the level of FⅫ: C and FⅫ: Ag at the same time. 3. As the human gene mutation database showed, the mutation records of FⅫ were only about 40 kinds. In the study, we found 5 novel mutations, which might provide an experimental basis to establish the diagnosis method and enhance the understanding of pathogenesis of FⅫ deficiency in the future.
学号	159001911
发布年限	2023-06-30
毕业论文分类号	R446
原始专题	第二临床医学院
学位论文研究方向	血栓与止血
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全文文件名	159001911李姗姗2020医学检验.pdf\|159001911李姗姗2020医学检验.pdf
文献类型	学位论文
条目标识符	https://kms.wmu.edu.cn/handle/3ETUA0LF/178174
专题	温州医科大学
作者单位	溫州医科大学第二临床医学院
第一作者单位	温州医科大学
推荐引用方式 GB/T 7714	李姗姗. 先天性凝血因子Ⅻ缺陷症的临床表型及基因分析[D]. 温州医科大学,2020.