Analysis of two propositas with inherited hypodysfibrinogenemia
10.3760/cma.j.cn114452-20220426-00254
- VernacularTitle:两个遗传性低且异常纤维蛋白原缺陷症家系分析
- Author:
Yuan CHEN
1
;
Kaiqi JIA
;
Anqing ZOU
;
Manlin ZENG
;
Lihong YANG
;
Jianrong YANG
;
Xiaolong LI
;
Yanhui JIN
;
Mingshan WANG
Author Information
1. 温州医科大学附属第一医院医学检验中心 浙江省检验诊断及转化研究重点实验室，温州325015
- Keywords:
Afibrinogenemia;
Mutation;
Compound heterozygous
- From:
Chinese Journal of Laboratory Medicine
2022;45(12):1207-1213
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To analyze the phenotype and genotype of two propositi with inherited hypodysfibrinogenaemia caused by compound heterozygous mutations, and investigate the molecular mechanism.Metheds:Two propositi and their family members(7 person in 3 generations and 10 person in 3 generations,respectively) were investigated. The activity of plasma fibrinogen (Fg:C) and thrombin time (TT) were analyzed by coagulation method, the antigen of plasma fibrinogen (Fg:Ag) was detected by immunoturbidimetry. All of the exons and flanking sequences of FGA,FGB,FGG of two propositi were amplified by PCR, followed by direct sequencing. The ClustalX-2, 1-win software was used to analyze the conservatism of mutated gene locus. PROVEAN and Mutation Taster were applied to analyze the pathogenicity of mutated amino acid. The changes of the protein spatial structure and intermolecular interaction were analyzed by Pymol.Results:Fg:C and Fg:Ag of proposita A and B were both significantly decreased (0.74 and 0.78 g/L, 0.96 and 0.94 g/L, respectively). Gene analysis revealed that proposita A and B both carried a heterozygous mutation c.2185G>A(p.AαGlu710Lys) in exon 6 of FGA. Furthermore, proposita A also carried a heterozygous mutation c.701G>T(p.γTrp208Leu) in exon 7 of FGG, and proposita B carried a heterozygous mutation c.1015A>C(p.γSer313Arg) in exon 8 of FGG. Phylogenetic analysis suggested that p.AαGlu710,p.γTrp208 and p.γSer313 were highly conserved among homologous species. All variants were predicted to be deleterious by two online bioinformatic softwares. The protein model analysis indicated that protein spatial structure and intermolecular hydrogen bonds were changed by these variants, which destroyed the stability of Fg.Conclusion:The compound heterozygous mutations of p.AαGlu710Lys and p.γTrp208Leu,p.AαGlu710Lys and p.γSer313Arg might account for the hypodysfibrinogenemia in two propositi.
