ZHOU Xingxing,LI Xiaolong,JIN Yanhui, et al. Genetic analysis of the pedigree with inherited coagulation factor XI deficiency caused by a homozygous Tyr503Cys mutation[J]. JOURNAL OF WEZHOU MEDICAL UNIVERSITY, 2019, 49(1): 30-33，37.
Abstract：Objective: To detect the phenotype and gene of a hereditary factor XI (FXI)-deficient pedigree caused by a homozygous Tyr503Cys missense mutation in search for the causative gene and exploration of its molecular pathogenesis. Methods: Prothrombin time (PT), activated partial thromboplastin time (APTT), coagulation factor VIII activity (FVIII:C), coagulation factor IX activity (FIX:C), coagulation factor XI activity (FXI:C), coagulation factor XII activity (FXII:C), and FXI antigen (FXI:Ag) were assayed in probands and their family members (five persons in three generations) to confirm the diagnosis. All exons and flanking sequences of the F11 gene of the proband were analyzed by direct PCR sequencing. The mutation sites were confirmed by reverse sequencing and the corresponding mutation site regions of the familial members were detected. The conservation of amino acid mutation sites was analyzed using ClustalX-2.1-win software; the effect of mutations on protein function was analyzed using PolyPhen-2, PROVEAN, and Mutation Taster software; the mutation site was analyzed by Swiss-PdbViewer software for protein model and amino acid interactions. Results: The APTT of proband was 59.3 s, prolonged obviously, and the FIX:C decreased to 13%; the APTT of mother, daughter and son were all prolonged to varying degrees, the FIX:C fell to 37%-42%, and the family of five people’s FXI:Ag were in the reference range. Genetic analysis revealed that there was a c.1562A>G homozygous missense mutation in exon 13 of the F11 gene in the proband, leading to Tyr503Cys; heterozygotes of the Tyr503Cys mutation existed in the mother, daughter, and son. Conservative analysis showed that Tyr503 is highly conserved among homologous species. The three bioinformatics software’s predictive results for this mutation were consistent: both predicted that this mutation was likely to be a deleterious mutation that could cause related diseases. Mutant protein model analysis showed that wild-type Tyr503 forms two hydrogen bonds with Ile370 and Lys554; a hydrogen bond was added between mutant Cys503 and Lys554. Conclusion: There was a c.1562A>G homozygous missense mutation in exon 13 of the F11 gene in the proband, laeding to Tyr503Cys. It was speculated that the homozygous mutation was inherited from a parent with a heterozygous Tyr503Cys homozygote and that it was associated with reduced FXI levels in the family.
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