Analysis of a pedigree affected with congenital dysfibrinogenemia due to heterozygous Gln195Arg mutation of fibrinogen γ chain gene
10.3760/cma.j.cn114452-20200405-00364
- VernacularTitle:一个纤维蛋白原γ链Gln195Arg突变所致的遗传性异常纤维蛋白原血症家系的分析
- Author:
Dandan HUANG
1
;
Ting CAI
;
Jing DAI
;
Qiulan DING
;
Xuefeng WANG
Author Information
1. 中国科学院大学宁波华美医院医学实验部，浙江省消化系统肿瘤诊治及研究重点实验室，中国科学院大学宁波生命与健康产业研究院，宁波 315000
- From:
Chinese Journal of Laboratory Medicine
2020;43(8):831-836
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To analyze the phenotype and genotype of a Chinese pedigree with congenital dysfibrinogenemia and investigate the molecular mechanism of the disease.Methods:Pedigree analysis. Peripheral blood samples were collected from 7 members of the pedigree and routine coagulation tests were conducted. The activity of fibrinogen was measured using Clauss method, and fibrinogen antigen was measured by immunoturbidimetry. All the exons and exon-intron boundaries of FGA, FGB and FGG genes were amplified using PCR, which was followed by direct sequencing. Electrophoretic and immunological analysis of fibrinogen, fibrinogen clottability measurement, fibrin polymerization measurement and scanning electron microscopy were used to investigate the pathogenesis of this disease. Results:The proband showed normal activated partial thromboplastin time (APTT) , prolonged prothrombin time(PT), thrombin time (TT),and reptilase time (RT).The antigen level of fibrinogen in the proband (1.6 g/L) decreased slightly, while the activity level of fibrinogen (0.7 g/L) decreased significantly. His father and grandmother showed normal APTT and PT, prolonged TT and RT. The antigen levels of fibrinogen in both of them were normal (2.0 g/L and 2.2 g/L, respectively), while the activity levels of fibrinogen were low (1.0 g/L and 1.1 g/L, respectively). The results of other members from the pedigree were all within the normal range. Genetic analysis revealed a heterozygous A>G mutation at nucleotide 4774 in exon 6 of FGG gene in the proband, which was predicated to be a novel Gln195Arg mutation. The mutation was also found in his father and grandmother.Western blot results showed that no abnormal bands of plasma fibrinogen were found in the proband, his father and grandmother. The fibrinogen clottability in the proband was 49.3%, while that in the heathy control was 98.9%. Both thrombin-induced fibrin polymerization and reptilase-induced fibrin polymerization were significantly impaired in the proband, compared to that in the heathy control. Scanning electron microscopy revealed that compared with the heathy control, the average fiber diameters of the fibrin clot in the proband increased significantly ( P<0.001), while the density of fibers decreased and the arrangement of fibers was sparse. Conclusions:The heterozygous Arg19Gly mutation, which probably damages functions of fibrinogen, should be responsible for the congenital dysfibrinogenemia in this pedigree. This mutation has not been reported.
