Analysis of hereditary coagulation factor Ⅺ deficiency in a Chinese pedigree with compound heterozygous mutations
10.3760/cma.j.cn511374-20201014-00718
- VernacularTitle:一个复合杂合变异致遗传性凝血因子Ⅺ缺陷症家系分析
- Author:
Yuping DENG
1
;
Yuxiang GONG
;
Jiajin ZHU
;
Xingxing ZHOU
;
Mingshan WANG
;
Wenhe WU
Author Information
1. 温州医科大学检验医学院（生命科学学院）检验医学教育部重点实验室，温州 325035
- Keywords:
Coagulation factor Ⅺ deficiency;
Molecular genetics;
Bioinformatics
- From:
Chinese Journal of Medical Genetics
2022;39(6):592-596
- CountryChina
- Language:Chinese
-
Abstract:
Objective:To explore the molecular mechanisms of a Chinese pedigree with hereditary factor Ⅺ (FⅪ) deficiency.Methods:All of the 15 exons, flanking sequences of the FⅪ gene and the corresponding mutation sites of family members were analyzed by the Sanger sequencing, followed by the extraction of the peripheral blood genomic DNA. And all the results were verified by the reverse sequencing. The conservation of the mutated sites was analyzed by the ClustalX-2.1-win. Three online bioinformatics software tools, including Mutation Taster, PolyPhen2 and the PROVEAN, were used to assess the possible impact of the mutations. Swiss-pdbviewer software was used to analyze the effects of mutant amino acids on protein structure.Results:Genetic analysis revealed that the proband had compound heterozygous mutations including a nonsense mutation of c. 1107C>A (Tyr369stop) in exon 10 and missense mutation of c. 1562A>G (Tyr521Cys) in exon 13. The same c. 1107C>A (Tyr369stop) was present in her father, the same c. 1562A>G (Tyr521Cys) was present in both her mother and daughter. Conservation analysis indicated that Tyr521 was a highly conserved site during evolution. The prediction of pathogenicity showed that both c. 1107C>A and c. 1562A>G were pathogenic mutations. Protein structure prediction showed that in the wild type FⅪ protein structure, Tyr521 formed a hydrogen bond with the Lys572 and Ile388, respectively. When Tyr521 was replaced by Cys521, the original benzene ring structure disappeared, and side chains of Lys572 added a hydrogen bond with the Cys521, which may chang protein catalytic domain structure. When Tyr369 was mutated to a stop codon, resulting in the truncated protein.Conclusion:The compound heterozygous mutations including the c. 1107C>A heterozygous missense variant in exon 10 and the c. 1562A>G heterozygous nonsense mutation in exon 13 may be responsible for the hereditary factor Ⅺ deficiency in this Chinese pedigree.
