CAJ | 학술논문

目的：对由同一突变位点导致的两个遗传性低纤维蛋白原血症家系进行临床表型和基因型分析，探讨其分子发病机制。方法：检测两个家系所有成员的血浆凝血酶原时间（PT）、活化部分凝血活酶时间（APTT）、凝血酶时间（TT）、纤溶酶原活性（PLG：C）和纤维蛋白（原）降解产物（FDPs），分别采用Clauss法与免疫比浊法测定血浆纤维蛋白原活性（Fg：C）和抗原（Fg：Ag）水平。提取DNA，PCR扩增Fg的FGA、FGB和FGG基因所有外显子和侧翼序列，PCR产物纯化后测序进行基因分析。采用Swiss-Model和PIC软件对突变位点进行蛋白模型和氨基酸相互作用的分析。结果：两家系先证者PT、APTT以及纤溶指标（PLG：C和FDPs）均在正常范围内，TT轻度延长；Fg：C明显降低，分别为0.49 g/L和0.63 g/L；Fg：Ag同步下降，分别为0.64 g/L和0.77 g/L。先证者A的奶奶和父亲，先证者B的母亲、阿姨和表弟，Fg：C和Fg：Ag均有不同程度降低。基因分析发现2例先证者FGG基因第7号外显子5792位发生G＞T杂合错义突变，导致Fg γD结构域的208位色氨酸突变为亮氨酸（γTrp208Leu）。模型分析显示γTrp208Leu突变破坏了Trp208与Thr314间的天然氢键连接，并使该位点氨基酸侧链变短，空间构型改变，使突变蛋白稳定性下降。结论：纤维蛋白原FGG基因γTrp208Leu杂合错义突变是导致该两个遗传性低纤维蛋白原血症的原因。
목적：대유동일돌변위점도치적량개유전성저섬유단백원혈증가계진행림상표형화기인형분석，탐토기분자발병궤제。방법：검측량개가계소유성원적혈장응혈매원시간（PT）、활화부분응혈활매시간（APTT）、응혈매시간（TT）、섬용매원활성（PLG：C）화섬유단백（원）강해산물（FDPs），분별채용Clauss법여면역비탁법측정혈장섬유단백원활성（Fg：C）화항원（Fg：Ag）수평。제취DNA，PCR확증Fg적FGA、FGB화FGG기인소유외현자화측익서렬，PCR산물순화후측서진행기인분석。채용Swiss-Model화PIC연건대돌변위점진행단백모형화안기산상호작용적분석。결과：량가계선증자PT、APTT이급섬용지표（PLG：C화FDPs）균재정상범위내，TT경도연장；Fg：C명현강저，분별위0.49 g/L화0.63 g/L；Fg：Ag동보하강，분별위0.64 g/L화0.77 g/L。선증자A적내내화부친，선증자B적모친、아이화표제，Fg：C화Fg：Ag균유불동정도강저。기인분석발현2례선증자FGG기인제7호외현자5792위발생G＞T잡합착의돌변，도치Fg γD결구역적208위색안산돌변위량안산（γTrp208Leu）。모형분석현시γTrp208Leu돌변파배료Trp208여Thr314간적천연경건련접，병사해위점안기산측련변단，공간구형개변，사돌변단백은정성하강。결론：섬유단백원FGG기인γTrp208Leu잡합착의돌변시도치해량개유전성저섬유단백원혈증적원인。
Objective: To analyze the phenotype and genotype of two Chinese pedigrees with inherited hypoifbrinogenemiaidentify by the same mutation.Methods: Laboratory tests, including prothrombin time (PT), activated partial thromboplastin time (APTT), thrombin time (TT), plasminogen activity (PLG:C), and ifbrinogen degradation products (FDPs) were detected in two pedigrees. The activity and antigen plasma ifbrinogen (Fg:C, Fg:Ag) were analyzed by Clauss and immunoturbidimetry methods respectively. All the exons and exon-intron boundaries of the three Fg genesFGA,FGB andFGC were ampliifed by PCR and followed by direct sequencing. The mutation was analyzed by the Swiss-Model and PIC.Results: Two probands had normal PT, APTT, PLG:A and FDPs, but slightly prolonged TT. The Fg:C of the two probands were signiifcantly reduced, 0.49 g/L and 0.63 g/L respectively. Their Fg:Ag were both signiifcantly reduced, 0.63 g/L and 0.77 g/L respectively. These abnor-malities were also found in his grandma and father of proband A, mother, aunt and cousin of proband B. Genetic analysis revealed a heterozygous G>T change at nucleotide 5792 in exon 7 ofFGG gene in the two probands, predicting a heterozygous Trp208Leu mutation. Model analysis showed that the Trp208Leu mutation is disrupted the native hydrogen bonding network of Thr314, and changed the molecular geometries, increasing instability of the protein.Conclusion: Inherited hypoifbrinogenemia in those two pedigrees were caused by heterozygous Trp208Leu mutation in the γ chain of Fg.