2例遗传性异常纤维蛋白原血症分子致病机制研究  

Molecular Pathogenic Mechanism Study of Two Cases of Inherited Dysfibrinogenemia

作　　者：王敏 陈天平 江傲霜 朱成琳 韦楠 朱丽娟 屈丽君 刘洪军 WANG Min;CHEN Tian-Ping;JIANG Ao-Shuang;ZHU Cheng-Lin;WEI Nan;ZHU Li-Juan;QU Li-Jun;LIU Hong-Jun(Department of Hematology&Oncology,Anhui Provincial Children's Hospital,Hefei 230022,Anhui Province,China;Department of Clinical Laboratory Examination,Anhui Provincial Children's Hospital,Hefei 230022,Anhui Province,China)

机构地区：[1]安徽省儿童医院血液肿瘤科,安徽合肥230022 [2]安徽省儿童医院检验科,安徽合肥230022

出　　处：《中国实验血液学杂志》2025年第1期187-192,共6页Journal of Experimental Hematology

基　　金：安徽省自然科学基金(2108085MH268)。

摘　　要：目的:对两个遗传性异常纤维蛋白原血症家系进行基因分析,探讨分子发病机制。方法:检测先证者及其家系成员凝血相关指标。用PCR法扩增纤维蛋白原FGA、FGB、FGG外显子及其侧翼序列,测序寻找突变位点;用SIFT、PolyPhen2、LRT、ReVe、MutationTaster、phyloP、phastCons生物信息学软件预测突变位点功能;用PyMOL和Clustal X分析变异蛋白质结构及氨基酸保守性。结果:家系1先证者凝血酶时间(TT)为37.00 s,纤维蛋白原活性(Fg∶C)降低至0.52 g/L;家系2先证者TT为20.30 s,Fg∶C低于正常范围,为1.00 g/L。基因分析结果显示,家系1先证者FGA基因存在c.80T>C杂合突变,导致27位苯丙氨酸突变为丝氨酸(Phe27Ser);家系2先证者FGG基因存在c.1007T>A杂合突变,导致336位甲硫氨酸突变为赖氨酸(Met336Lys)。生物信息学软件预测分析提示两个变异均为有害变异;PyMOL突变模型提示,家系1先证者Aα链Phe27Ser和家系2先证者γ链Met336Lys,引起空间结构改变,导致蛋白稳定性降低;Clustal X结果显示,Aα链Phe27和γ链Met336在同源物种间高度保守。结论:FGA基因c.80T>C及FGG基因c.1007T>A杂合突变,均为致病性变异,引起遗传性异常纤维蛋白原血症。Objective: To analyze two families with inherited dysfibrinogenemia, and explore the molecular pathogenic mechanisms. Methods: The coagulation indexes of the probands and their family members were detected. The FGA, FGB, and FGG exons and their flanking sequences were amplified by PCR, and the mutation sites were identified by sequencing. SIFT, PolyPhen2, LRT, ReVe, MutationTaster, phyloP, and phastCons bioinformatics software were used to predict the functional impact of the mutation sites. Protein structure and amino acid conservation analysis of the variant were conducted using PyMOL and Clustal X software. Results: The thrombin time(TT) of the proband in family 1 was prolonged to 37.00 s, and Fg∶C decreased to 0.52 g/L. The TT of the proband in family 2 was 20.30 s, and Fg∶C was 1.00 g/L, which was lower than the normal range. Genetic analysis revealed that the proband in family 1 had a heterozygous mutation c.80T>C in FGA, resulting in the substitution of phenylalanine 27 with serine(Phe27Ser). The proband in family 2 had a heterozygous mutation c.1007T>A in FGG, resulting in the substitution of methionine 336 with lysine(Met336Lys). Bioinformatics software prediction analysis indicated that both mutations were deleterious variants. PyMOL mutation models revealed that the Aα chain mutation(Phe27Ser) in family 1 and γ chain mutation(Met336Lys) in family 2 resulted in alterations in spatial structure and reduced protein stability. Clustal X results showed that both Aα Phe27 and γMet336 were highly conserved across homologous species. Conclusion: Heterozygous mutations of FGA gene c.80T>C and FGG gene c.1007T>A are both pathogenic variants, causing inherited dysfibrinogenemia.

关 键 词：FGA基因 FGG基因 遗传性异常纤维蛋白原血症 纤维蛋白原 基因突变 

分 类 号：R554.5[医药卫生—血液循环系统疾病] R596[医药卫生—内科学]