Molecular defects in the factor X gene caused by novel heterozygous mutations IVS5+1G > A and Asp409del
文献类型：期刊论文
| 作者 | Zhou, J. W.1,4; Liang, Q.1; Chen, Q.1; Xie, Y.1,3; Ding, Q. L.2; Wang, X. F.2; Xi, X. D.1; Wang, H. L.1 |
| 刊名 | HAEMOPHILIA
 |
| 出版日期 | 2013-01 |
| 卷号 | 19期号:1页码:94-99 |
| 关键词 | bleeding disorder factor X deficiency molecular modelling splice-site mutation type II deficiency |
| ISSN号 | 1351-8216 |
| DOI | 10.1111/j.1365-2516.2012.02933.x |
| 文献子类 | Article |
| 英文摘要 | Factor X (FX) deficiency is a rare autosomal-recessive bleeding disorder caused by diverse mutations in the F10 gene. To investigate the molecular basis of severe FX deficiency in a mildly hemorrhagic patient, variants of the F10 gene were detected by sequencing. A missense mutation was analysed by in vitro expression and modelling analysis, and a splice mutation using ectopic transcript analysis. The levels of activity of FX (FX:C) were <1% in both intrinsic and extrinsic pathway assays and 1.71% in chromogenic assay, the level of FX antigen (FX:Ag) was 53.36% in the proband. Two novel heterozygous mutations (IVS5+1G>A and Asp409del) were identified in the F10 gene. Ectopic transcript expression combined with informative marker (heterozygous Asp409del) analysis of the splice mutation (IVS5+1G>A) revealed and confirmed that the transcript from the mutated allele was absent, likely caused by the nonsense-mediated mRNA decay pathway. In vitro expression analysis showed that the Asp409del mutant led to a loss of enzymatic activity rather than impaired expression. Molecular modelling analysis confirmed that the Asp409del mutant dramatically altered the conformation of the 185-189 loop and impaired binding of the loop to sodium ions (Na+), diminishing the enzymatic activity of FXa. This is the first report to clarify the molecular mechanisms of two naturally occurring F10 gene variants that cause severe FX deficiency. |
| WOS关键词 | DEFICIENCY ; PHENOTYPE |
| WOS研究方向 | Hematology |
| 语种 | 英语 |
| WOS记录号 | WOS:000314827200022 |
| 出版者 | WILEY-BLACKWELL |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/277816]  |
| 专题 | 新药研究国家重点实验室 中科院受体结构与功能重点实验室 |
| 通讯作者 | Ding, Q. L. |
| 作者单位 | 1.Shanghai Inst Hematol, State Key Lab Med Genom, Shanghai, Peoples R China; 2.Shanghai Jiao Tong Univ, Ruijin Hosp, Dept Lab Med, Sch Med, Shanghai 200025, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Drug Discovery & Design Ctr, Shanghai 200031, Peoples R China; 4.Zhejiang Univ, Affiliated Hosp 1, Coll Med, State Key Lab Diag & Treatment Infect Dis, Hangzhou 310003, Zhejiang, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Zhou, J. W.,Liang, Q.,Chen, Q.,et al. Molecular defects in the factor X gene caused by novel heterozygous mutations IVS5+1G > A and Asp409del[J]. HAEMOPHILIA,2013,19(1):94-99. |
| APA | Zhou, J. W..,Liang, Q..,Chen, Q..,Xie, Y..,Ding, Q. L..,...&Wang, H. L..(2013).Molecular defects in the factor X gene caused by novel heterozygous mutations IVS5+1G > A and Asp409del.HAEMOPHILIA,19(1),94-99. |
| MLA | Zhou, J. W.,et al."Molecular defects in the factor X gene caused by novel heterozygous mutations IVS5+1G > A and Asp409del".HAEMOPHILIA 19.1(2013):94-99. |
入库方式： OAI收割
来源：上海药物研究所
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