纤维蛋白原γ链Ile171His突变导致遗传性低纤维蛋白原血症家系研究

Fibrinogen gamma-chain mutation, p.Ile171His, leads to hereditary hypofibrinogenemia

目的对一个遗传性低纤维蛋白原血症家系进行临床表型和基因型研究,并探讨其分子发病机制。方法抽取于2018年12月至2019年10月就诊于北京大学国际医院的全部家系成员外周血,检测活化部分凝血活酶时间、凝血酶原时间、凝血酶时间和血栓弹力图。纤维蛋白原活性和抗原分别用Clauss法和免疫比浊法检测。PCR扩增纤维蛋白原基因FGA、FGB和FGG所有外显子及其侧翼序列,PCR产物纯化后直接测序进行基因分析。结果先证者凝血酶原时间(15.2 s)、凝血酶时间(18.7 s)延长,纤维蛋白原活性(1.60 g/L)及抗原(1.61 g/L)成比例降低;血栓弹力图显示K值(4.8 min)延长,Angle值(42.3°)减小。先证者父亲、女儿、儿子、哥哥及先证者哥哥幼女检测结果与之相似。先证者FGG基因的第5外显子存在c.510;12发生微小缺失突变。结论新发现的FGG基因第5外显子c.510;12del(Gln170;le171 del ins His)杂合错义突变是导致本研究家系遗传性低纤维蛋白原血症发生的分子机制。

Objective To explore the clinical phenotype and genotype of a family with hereditary hypofibrinogenemia.Methods Activated partial thrombin time(APTT),prothrombin time(PT),thrombin time(TT)and thrombelastogram(TEG)were tested in all family members.Fibrinogen activity and antigen were detected by Clauss method and immunoturbidimetric method respectively.All exons and flanking sequences of fibrinogen FGA,FGB,FGG genes were analyzed by PCR,and the products were subjected to Sanger sequencing.Results The proband represented prolonged PT and TT,low Fg activity and antigen,elevated K value and decreased Angle value in TEG.Other family members reported similar changes including proband′s father,daughter and son,and his elder brother and his niece.Exon 5 c.510_512 of FGG gene in the proband revealed a minor deletion mutation.Conclusion The novel heterozygous missense mutation of exon 5 c.510_512del(Gln170_Ile171 del ins His)of FGG gene is the molecular mechanism that leads to hereditary hypofibrinogenemia in this family.