Analysis of a pedigree causing by compound heterozygous mutation with hereditary coagulation factor Ⅺ deficiency
Objective To examine the physical characteristics and genetic composition of a family affected by he-reditary coagulation factor Ⅺ deficiency,and to explore the underlying molecular mechanisms causing this condition.Methods Prothrombin time(PT),activated partial thromboplastin time(APTT),and the activity of coagulation factors Ⅷ,Ⅸ,Ⅺ,and Ⅻ were assessed using coagulation methods.The enzyme-linked immunosorbent assay was employed to detect the coagulation factor Ⅺ antigen.Sanger sequencing was employed to analyze exons and their flanking sequences of the F11 gene.Homolog conservation analysis of the mutation sites was conducted using Clustalx-2.1-win.The Mutation Taster online bio-informatics software was used to forecast the mutations harmfulness.Simulation and construction of the mutated protein structure were carried out using PyMOLWin.Results The proband exhibited a significantly prolonged APTT of 76.8 s,with a notable decrease in both coagulation factor Ⅺ activity(2％)and antigen(4％).Genotypic analysis identified two heterozygous nonsense mutations in exon 7 c.738G＞A(p.Trp228stop)and exon 13 c.1556G＞A(p.Trp501stop)of the F11 gene in proband.Conservation analysis showed that Trp228 and Trp501 were highly conserved among seven homologous specie.Online bioin-formatics analysis showed that both mutations were harmful.Protein model revealed that both mutations produced truncated proteins,leading to a loss of structural integrity.Conclusion The p.Trp228stop and p.Trp501stop nonsense mutations could be the molecular pathogenesis of coagulation factor Ⅺ deficiency in the proband and his family members.
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