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| 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
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| Cite this article: |
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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.
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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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Received: 14 June 2016
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[1] BUTENAS S, DEE J D, MANN K G. The function of factor XI intissue factor-initiated thrombin generation[J]. J Thromb Haemost, 2003, 1(10): 2103-2111.
[2] SOUABNI L, MEDDEB N, AJLANI H, et al. Hemarthrosis revealing congenital factor XI deficiency[J]. Joint Bone Spine, 2008, 75(3): 348-349.
[3] 武文漫, 王鸿利. 遗传性凝血因子XI缺陷的分子发病机制研究进展[J]. 血栓与止血学, 2004, 10(4): 181-184.
[4] EMSLEY J, MCEWAN P A, GAILANI D. Structure and function of factor XI[J]. Blood, 2010, 115(13): 2569-2577.
[5] ASAKAI R, CHUNG D W, RATNOFF O D, et al. Faetor XI (plasma thromboplastin antecedent) deficiency in Ashkenazi Jews is a bleeding disorder that can result from three types of point mutations[J]. Proc Natl Acad Sci U S A, 1989, 86(20): 7667-7671.
[6] 武文漫, 王鸿利, 王学锋, 等. 两种新的无义突变Trp228stop和Trp283stop导致的遗传性凝血因子XI缺陷症[J]. 中华血液学杂志, 2003, 24(3): 126-128.
[7] GOMEZ K, BOLTON-MAGGS P. Factor XI deficiency[J].Haemophilia, 2008, 14(6): 1183-1189.
[8] 戴利亚, 张德亭, 谢海啸. 一个遗传性凝血因子XI缺陷症家系的基因分析[J]. 温州医科大学学报, 2015, 45(5): 376-380.
[9] ZHANG H, LÖWENBERG E C, CROSBY J R, et al. Inhibition of the intrinsic coagulation pathway factor XI by antisense oligonucleotides: a novel antithrombotic strategy with lowered bleeding risk[J]. Blood, 2010, 116(22): 4684-4692.
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