Dysfibrinogenemia-associated novel heterozygous mutation, Shanghai (FGA c.169_180+2 del), leads to N-terminal truncation of fibrinogen Aα chain and impairs fibrin polymerization
Dysfibrinogenemia-associated novel heterozygous mutation, Shanghai (FGA c.169_180+2 del), leads to N-terminal truncation of fibrinogen Aα chain and impairs fibrin polymerization
复制标题
与纤维蛋白原血症相关的新型杂合突变，上海（FGA c.169_180 2 del），导致纤维蛋白原 Aα 链 N 端截断并损害纤维蛋白聚合
DOI：
10.1136/jclinpath-2016-203862
复制
发表时间：
2016-08
期刊：
影响因子：
--
通讯作者：
戴菁
中科院分区：
文献类型：
--
作者：
戴菁
目的 在患有抗磷脂抗体综合征 (APS) 和复发性静脉血栓形成的异常纤维蛋白原血症患者及其无症状父亲中鉴定出一种新的杂合变异体 FGA c.169_180+2 del（称为纤维蛋白原上海）。我们的目的是揭示这种变体引起的结构变化的功能含义。方法采用FGA小基因转染实验进行转录分析，评估核苷缺失对mRNA编辑的影响。从前列腺血浆中分离出的纤维蛋白原用于表征其功能缺陷。通过光学测量浊度进行纤维蛋白聚合和凝块溶解实验。通过反相高效液相色谱分析凝血酶催化的纤维蛋白肽释放。通过扫描电子显微镜观察纤维蛋白凝块的超微结构。结果 FGA c.169_180+2 del 导致外显子 2 跳跃的异常 mRNA，并编码 N 末端有 42 个氨基酸截短的缩短的 Aα 链。 Propositus 的纤维蛋白原的纤维蛋白肽 A 释放受损，聚合异常，滞后时间显着延长，最大斜率变慢，最终浊度降低。由Propositus纤维蛋白原形成的纤维蛋白凝块显示出较粗的纤维和较疏松的网络结构。使用纯化的纤维蛋白原时，血块溶解是正常的，但与来自他父亲的血浆样本相比，使用来自产妇的血浆样本时，血块溶解明显受损。结论 纤维蛋白原上海导致Aα链N端截短，不会干扰纤维蛋白原的合成、组装或分泌，但会影响纤维蛋白聚合和凝块形成。 APS 至少部分促进了前列腺中血栓形成的发生。
Aims A novel heterozygous variant, FGA c.169_180+2 del (designated fibrinogen Shanghai), was identified in a patient with dysfibrinogenemia with antiphospholipid antibody syndrome (APS) and recurrent venous thrombosis, and in his asymptomatic father. We aimed to reveal the functional implication of structural change caused by this variant. Methods Transcription analysis was performed with FGA minigene transfection assay to evaluate the impact of nucleosides deletion on mRNA editing. The fibrinogen isolated from propositus' plasma was used to characterise its functional defects. Fibrin polymerization and clot lysis experiments were performed by optical measurement of turbidity. Thrombin-catalysed fibrinopeptide release was analysed by the reversed-phase, high-performance liquid chromatography. The ultrastructures of fibrin clots were visualised by scanning electron microscopy. Results FGA c.169_180+2 del led to an aberrant mRNA with exon 2 skipping and encoded an shortened Aα chain with 42 amino acids truncation at its N-terminal. The propositus' fibrinogen had an impaired release of fibrinopeptide A and abnormal polymerization with a significantly prolonged lag time, a slower maximum slope and reduced final turbidity. The fibrin clot formed with propositus' fibrinogen showed thicker fibres with looser network structure. Clot lysis was normal using the purified fibrinogen but was significantly impaired using the plasma sample from propositus, compared with that from his father. Conclusions Fibrinogen Shanghai results in N-terminal truncation of Aα chain, which does not interfere with synthesis, assembly or secretion of fibrinogen, but compromises fibrin polymerization and clot formation. APS at least partially contributes to the development of thrombosis in the propositus.
登录
查看更多内容
影响因子：
--
作者：
W. Seegers;J. F. Johnson;C. Fell
通讯作者：
W. Seegers;J. F. Johnson;C. Fell
影响因子：
20.3
作者：
Jennifer L. Moen;O. Gorkun;J. Weisel;S. Lord
通讯作者：
Jennifer L. Moen;O. Gorkun;J. Weisel;S. Lord
影响因子：
6.7
作者：
J. Hettasch;M. Bolyard;S. Lord
通讯作者：
J. Hettasch;M. Bolyard;S. Lord
影响因子：
1.1
作者：
Yuka Kamijyo;M. Hirota-Kawadobora;K. Yamauchi;F. Terasawa;T. Honda;M. Ikeya;N. Okumura
通讯作者：
Yuka Kamijyo;M. Hirota-Kawadobora;K. Yamauchi;F. Terasawa;T. Honda;M. Ikeya;N. Okumura
影响因子：
6.7
作者：
C. Binnie;S. Lord
通讯作者：
C. Binnie;S. Lord