Phenotypic diagnosis and genetic analysis in a proband with hereditary coagulation factor XI deficiency
YE Jiajia1, YANG Lihong1, HaoXiuping1, CHEN Bicheng2.
1.Department of Laboratory, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325015; 2.Surgical Laboratory, the First Affiliated Hospital of Wenzhou Medicatl University, Wenzhou, 325015
YE Jiajia,YANG Lihong,HaoXiuping, et al. Phenotypic diagnosis and genetic analysis in a proband with hereditary coagulation factor XI deficiency[J]. JOURNAL OF WEZHOU MEDICAL UNIVERSITY, 2017, 47(5): 356-360.
Abstract：Objective: To identify potential mutations and explore the molecular mechanism of a proband underlying hereditary coagulation factor XI (FXI) deficiency. Methods: Clinical diagnosis was validated by measuring the prothrombin time (PT), activated partial thromboplastin time (APTT), fibrinogen, FXI activity (FXI:C) and FXI antigen (FXI:Ag). Potential mutations of FXI gene were analyzed by PCR and direct DNA sequencing. Suspected mutations were confirmed by sequencing the opposite strand. With the aid of bioinformatics software PyMOL Viewer1.5.x, the wild-type and mutant FXI protein model was also comparatively analyzed. Results: The results of APTT, FXI:C, FXI:Ag in the proband and her brother were obviously abnormal, 78.4 s, 2.0%, 6.8% and 62.1 s, 4.5%, 10.0% respectively. The FXI:C and FXI:Ag of her other family member also presented with different degrees of reduction. A heterozygous g.15410G>A in exon 6 and g.25471C>G in exon 12 were identified, resulting in the nonsense mutation Trp228stop and missense mutation Cys482Trp. Her father, sister, niece were heterozygous for Trp228stop, while her mother and nephew were for the Cys482Trp mutation. Modeling showed that the missense mutation did not destroy the natural hydrogen bonds, however, it lead to the formation of the space steric hindrance with amino acids 267 which will change the protein structure. Conclusion: A heterozygous Trp228stop mutation and a heterozygous Cys482Trp mutation have been identified in the FXI gene, which can explain the low levels of the FXI:C and FXI:Ag in the proband.
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