• 文献检索
  • 文档翻译
  • 深度研究
  • 学术资讯
  • Suppr Zotero 插件Zotero 插件
  • 邀请有礼
  • 套餐&价格
  • 历史记录
应用&插件
Suppr Zotero 插件Zotero 插件浏览器插件Mac 客户端Windows 客户端微信小程序
定价
高级版会员购买积分包购买API积分包
服务
文献检索文档翻译深度研究API 文档MCP 服务
关于我们
关于 Suppr公司介绍联系我们用户协议隐私条款
关注我们

Suppr 超能文献

核心技术专利:CN118964589B侵权必究
粤ICP备2023148730 号-1Suppr @ 2026

文献检索

告别复杂PubMed语法,用中文像聊天一样搜索,搜遍4000万医学文献。AI智能推荐,让科研检索更轻松。

立即免费搜索

文件翻译

保留排版,准确专业,支持PDF/Word/PPT等文件格式,支持 12+语言互译。

免费翻译文档

深度研究

AI帮你快速写综述,25分钟生成高质量综述,智能提取关键信息,辅助科研写作。

立即免费体验

血管性血友病因子在血管性血友病中异常剪接的特征:一种未被充分认识的机制

Characterization of aberrant splicing of von Willebrand factor in von Willebrand disease: an underrecognized mechanism.

作者信息

Hawke Lindsey, Bowman Mackenzie L, Poon Man-Chiu, Scully Mary-Frances, Rivard Georges-Etienne, James Paula D

机构信息

Department of Pathology and Molecular Medicine and.

Department of Medicine, Queen's University, Kingston, ON, Canada;

出版信息

Blood. 2016 Jul 28;128(4):584-93. doi: 10.1182/blood-2015-10-678052. Epub 2016 Jun 17.

DOI:10.1182/blood-2015-10-678052
PMID:27317792
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4965908/
Abstract

Approximately 10% of von Willebrand factor (VWF) gene mutations are thought to alter messenger RNA (mRNA) splicing through disruption of consensus splice sites. This mechanism is likely underrecognized and affected by mutations outside consensus splice sites. During VWF synthesis, splicing abnormalities lead to qualitative defects or quantitative deficiencies in VWF. This study investigated the pathologic mechanism acting in 3 von Willebrand disease (VWD) families with putative splicing mutations using patient-derived blood outgrowth endothelial cells (BOECs) and a heterologous human embryonic kidney (HEK 293(T)) cell model. The exonic mutation c.3538G>A causes 3 in-frame splicing variants (23del, 26del, and 23/26del) which cannot bind platelets, blood coagulation factor VIII, or collagen, causing VWD through dominant-negative intracellular retention of coexpressed wild-type (WT) VWF, and increased trafficking to lysosomes. Individuals heterozygous for the c.5842+1G>C mutation produce exon 33 skipping, exons 33-34 skipping, and WT VWF transcripts. Pathogenic intracellular retention of VWF lacking exons 33-34 causes their VWD. The branch site mutation c.6599-20A>T causes type 1 VWD through mRNA degradation of exon 38 skipping transcripts. Splicing ratios of aberrant transcripts and coexpressed WT were altered in the BOECs with exposure to shear stress. This study provides evidence of mutations outside consensus splice sites disrupting splicing and introduces the concept that VWF splicing is affected by shear stress on endothelial cells.

摘要

约10%的血管性血友病因子(VWF)基因突变被认为通过破坏共有剪接位点来改变信使核糖核酸(mRNA)剪接。这种机制可能未得到充分认识,且会受到共有剪接位点以外的突变影响。在VWF合成过程中,剪接异常会导致VWF出现质量缺陷或数量不足。本研究使用患者来源的血液生成内皮细胞(BOECs)和异源人胚肾(HEK 293(T))细胞模型,研究了3个疑似存在剪接突变的血管性血友病(VWD)家系中的病理机制。外显子突变c.3538G>A导致3种框内剪接变体(23del、26del和23/26del),这些变体无法结合血小板、凝血因子VIII或胶原蛋白,通过共表达的野生型(WT)VWF的显性负性细胞内滞留以及增加向溶酶体的转运导致VWD。c.5842+1G>C突变的杂合个体产生外显子33跳跃、外显子33 - 34跳跃和WT VWF转录本。缺乏外显子33 - 34的VWF的致病性细胞内滞留导致他们患VWD。分支位点突变c.6599 - 20A>T通过外显子38跳跃转录本的mRNA降解导致1型VWD。暴露于剪切应力的BOECs中异常转录本与共表达的WT的剪接比率发生了改变。本研究提供了共有剪接位点以外的突变破坏剪接的证据,并引入了VWF剪接受内皮细胞剪切应力影响的概念。

相似文献

1
Characterization of aberrant splicing of von Willebrand factor in von Willebrand disease: an underrecognized mechanism.血管性血友病因子在血管性血友病中异常剪接的特征:一种未被充分认识的机制
Blood. 2016 Jul 28;128(4):584-93. doi: 10.1182/blood-2015-10-678052. Epub 2016 Jun 17.
2
Combined partial exon skipping and cryptic splice site activation as a new molecular mechanism for recessive type 1 von Willebrand disease.联合部分外显子跳跃和隐蔽剪接位点激活作为1型遗传性血管性血友病隐性型的一种新分子机制。
Thromb Haemost. 2006 Dec;96(6):711-6.
3
A synonymous (c.3390C>T) or a splice-site (c.3380-2A>G) mutation causes exon 26 skipping in four patients with von Willebrand disease (2A/IIE).一个同义突变(c.3390C>T)或剪接位点突变(c.3380-2A>G)导致了四名血管性血友病患者(2A/IIE)外显子 26 的跳跃。
J Thromb Haemost. 2013 Jul;11(7):1251-9. doi: 10.1111/jth.12280.
4
Severe, recessive type 1 is a discrete form of von Willebrand disease: the lesson learned from the c.1534-3C>A von Willebrand factor mutation.严重的1型隐性血管性血友病是血管性血友病的一种离散形式:从c.1534-3C>A血管性血友病因子突变中吸取的教训。
Thromb Res. 2015 Sep;136(3):682-6. doi: 10.1016/j.thromres.2015.07.014. Epub 2015 Jul 26.
5
Mutation distribution in the von Willebrand factor gene related to the different von Willebrand disease (VWD) types in a cohort of VWD patients.与不同血管性血友病 (VWD) 类型相关的血管性血友病因子基因中的突变分布在 VWD 患者队列中。
Thromb Haemost. 2012 Oct;108(4):662-71. doi: 10.1160/TH12-02-0089. Epub 2012 Aug 7.
6
A noncanonical splicing variant c.875-5 T > G in von Willebrand factor causes in-frame exon skipping and type 2A von Willebrand disease.一种非规范剪接变异 c.875-5T>G 在血管性血友病因子中导致框内外显子跳跃和 2A 型血管性血友病。
Thromb Res. 2024 Apr;236:51-60. doi: 10.1016/j.thromres.2024.02.002. Epub 2024 Feb 5.
7
Alterations of mRNA processing and stability as a pathogenic mechanism in von Willebrand factor quantitative deficiencies.mRNA 加工和稳定性改变作为 von Willebrand 因子定量缺陷的致病机制。
J Thromb Haemost. 2010 Dec;8(12):2736-42. doi: 10.1111/j.1538-7836.2010.04060.x.
8
Intron retention resulting from a silent mutation in the VWF gene that structurally influences the 5' splice site.由于血管性血友病因子(VWF)基因中的沉默突变导致内含子保留,该突变在结构上影响5'剪接位点。
Blood. 2016 Oct 27;128(17):2144-2152. doi: 10.1182/blood-2016-02-699686. Epub 2016 Aug 19.
9
Unraveling the effect of silent, intronic and missense mutations on splicing: contribution of next generation sequencing in the study of mRNA.解析沉默突变、内含子突变和错义突变对剪接的影响:下一代测序在 mRNA 研究中的贡献。
Haematologica. 2019 Mar;104(3):587-598. doi: 10.3324/haematol.2018.203166. Epub 2018 Oct 25.
10
Cellular and molecular basis of von Willebrand disease: studies on blood outgrowth endothelial cells.血管性血友病的细胞和分子基础:血衍生的内皮细胞研究。
Blood. 2013 Apr 4;121(14):2773-84. doi: 10.1182/blood-2012-06-435727. Epub 2013 Jan 25.

引用本文的文献

1
Multimodal Learning for Mapping the Genotype-Phenotype Dynamics.用于绘制基因型-表型动态图谱的多模态学习
Res Sq. 2024 May 16:rs.3.rs-4355413. doi: 10.21203/rs.3.rs-4355413/v1.
2
Identification of von Willebrand factor D4 domain mutations in patients of Afro-Caribbean descent: In vitro characterization.非洲加勒比裔患者血管性血友病因子D4结构域突变的鉴定:体外特性研究
Res Pract Thromb Haemost. 2022 Jun 15;6(4):e12737. doi: 10.1002/rth2.12737. eCollection 2022 May.
3
von Willebrand factor propeptide variants lead to impaired storage and ER retention in patient-derived endothelial colony-forming cells.血管性血友病因子前肽变异导致患者来源的内皮细胞集落形成细胞储存和内质网滞留受损。
J Thromb Haemost. 2022 Jul;20(7):1599-1609. doi: 10.1111/jth.15740. Epub 2022 May 3.
4
A Homozygous Deep Intronic Variant Causes Von Willebrand Factor Deficiency and Lack of Endothelial-Specific Secretory Organelles, Weibel-Palade Bodies.一种纯合性深内含子变异导致血管性血友病因子缺乏和缺乏内皮细胞特异性分泌细胞器,Weibel-Palade 小体。
Int J Mol Sci. 2022 Mar 13;23(6):3095. doi: 10.3390/ijms23063095.
5
Single-cell transcriptional analysis of human endothelial colony-forming cells from patients with low VWF levels.人类低血管性血友病因子水平患者的内皮祖细胞的单细胞转录组分析。
Blood. 2022 Apr 7;139(14):2240-2251. doi: 10.1182/blood.2021010683.
6
Multifaceted pathomolecular mechanism of a VWF large deletion involved in the pathogenesis of severe VWD.涉及严重 VWD 发病机制的 VWF 大片段缺失的多方面病理分子机制。
Blood Adv. 2022 Feb 8;6(3):1038-1053. doi: 10.1182/bloodadvances.2021005895.
7
Von Willebrand Disease: From In Vivo to In Vitro Disease Models.血管性血友病:从体内到体外疾病模型
Hemasphere. 2019 Sep 27;3(5):e297. doi: 10.1097/HS9.0000000000000297. eCollection 2019 Oct.
8
Variability of von Willebrand factor-related parameters in endothelial colony forming cells.血管内皮祖细胞中血管性血友病因子相关参数的变异性。
J Thromb Haemost. 2019 Sep;17(9):1544-1554. doi: 10.1111/jth.14558. Epub 2019 Jul 22.
9
Unraveling the effect of silent, intronic and missense mutations on splicing: contribution of next generation sequencing in the study of mRNA.解析沉默突变、内含子突变和错义突变对剪接的影响:下一代测序在 mRNA 研究中的贡献。
Haematologica. 2019 Mar;104(3):587-598. doi: 10.3324/haematol.2018.203166. Epub 2018 Oct 25.
10
Discrepant platelet and plasma von Willebrand factor in von Willebrand disease patients with p.Pro2808Leufs*24.血管性血友病患者 p.Pro2808Leufs*24 存在血小板和血浆血管性血友病因子的差异。
J Thromb Haemost. 2017 Jul;15(7):1403-1411. doi: 10.1111/jth.13722. Epub 2017 Jun 6.

本文引用的文献

1
von Willebrand disease type 2A phenotypes IIC, IID and IIE: A day in the life of shear-stressed mutant von Willebrand factor.2A型血管性血友病IIC、IID和IIE亚型:剪切应力作用下突变血管性血友病因子的一天。
Thromb Haemost. 2014 Jul 3;112(1):96-108. doi: 10.1160/TH13-11-0902. Epub 2014 Mar 6.
2
A synonymous (c.3390C>T) or a splice-site (c.3380-2A>G) mutation causes exon 26 skipping in four patients with von Willebrand disease (2A/IIE).一个同义突变(c.3390C>T)或剪接位点突变(c.3380-2A>G)导致了四名血管性血友病患者(2A/IIE)外显子 26 的跳跃。
J Thromb Haemost. 2013 Jul;11(7):1251-9. doi: 10.1111/jth.12280.
3
Alternative splicing: a pivotal step between eukaryotic transcription and translation.可变剪接:真核转录与翻译之间的关键步骤。
Nat Rev Mol Cell Biol. 2013 Mar;14(3):153-65. doi: 10.1038/nrm3525. Epub 2013 Feb 6.
4
Cellular and molecular basis of von Willebrand disease: studies on blood outgrowth endothelial cells.血管性血友病的细胞和分子基础:血衍生的内皮细胞研究。
Blood. 2013 Apr 4;121(14):2773-84. doi: 10.1182/blood-2012-06-435727. Epub 2013 Jan 25.
5
The genetics of Canadian type 3 von Willebrand disease: further evidence for co-dominant inheritance of mutant alleles.加拿大 3 型血管性血友病的遗传学:突变等位基因共显性遗传的进一步证据。
J Thromb Haemost. 2013 Mar;11(3):512-20. doi: 10.1111/jth.12130.
6
Sequence and structure relationships within von Willebrand factor.血管性血友病因子的序列和结构关系。
Blood. 2012 Jul 12;120(2):449-58. doi: 10.1182/blood-2012-01-405134. Epub 2012 Apr 6.
7
The study of the effect of splicing mutations in von Willebrand factor using RNA isolated from patients' platelets and leukocytes.利用从患者血小板和白细胞中分离的 RNA 研究 von Willebrand 因子剪接突变的影响。
J Thromb Haemost. 2011 Apr;9(4):679-88. doi: 10.1111/j.1538-7836.2011.04204.x.
8
A practical guide to evaluating colocalization in biological microscopy.生物显微镜共定位评估的实用指南
Am J Physiol Cell Physiol. 2011 Apr;300(4):C723-42. doi: 10.1152/ajpcell.00462.2010. Epub 2011 Jan 5.
9
Endothelial von Willebrand factor regulates angiogenesis.内皮型血管性血友病因子调节血管生成。
Blood. 2011 Jan 20;117(3):1071-80. doi: 10.1182/blood-2010-01-264507. Epub 2010 Nov 3.
10
Deciphering the splicing code.解读剪接码。
Nature. 2010 May 6;465(7294):53-9. doi: 10.1038/nature09000.