Identification of a homozygous recessive variant in PTGS1 resulting in a congenital aspirin-like defect in platelet function.
Identification of a homozygous recessive variant in PTGS1 resulting in a congenital aspirin-like defect in platelet function.
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DOI：
10.3324/haematol.2019.235895
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发表时间：
2021-05-01
期刊：
影响因子：
10.1
通讯作者：
Warner TD
中科院分区：
文献类型：
--
作者：
Chan MV;Hayman MA;Sivapalaratnam S;Crescente M;Allan HE;Edin ML;Zeldin DC;Milne GL;Stephens J;Greene D;Hanif M;O'Donnell VB;Dong L;Malkowski MG;Lentaigne C;Wedderburn K;Stubbs M;Downes K;Ouwehand WH;Turro E;BioResource N;Hart DP;Freson K;Laffan MA;Warner TD
我们在9号染色体上发现了一个罕见的错义变异，位于前列腺素内过氧化物合成酶1 (PTGS1)（编码环加氧酶1 [COX-1]的基因，抗血栓阿司匹林治疗的靶标）的第8外显子125145990 （GRCh37）位置。我们报道，在一个大血缘家族的纯合子状态下，这种变异与出血表型、血小板反应性和类二十烷酸产生的改变有关。Western blotting和共聚焦成像显示，COX-1在PTGS1纯合子的三个家族成员的血小板中不存在，但在他们的白细胞中存在。通过聚集体、光聚集体和流式细胞术评估，纯合子家族成员的血小板反应性受损，血小板粘附和扩散也受损。受刺激的血小板产生的cox衍生的类二十烷酸大大减少，但尿中cox衍生的类二十烷酸代谢物的水平没有变化。先证在血小板聚集和扩散方面表现出额外的缺陷，这可能解释了为什么她的出血表型比其他纯合子患病亲属略严重。这是人类首次证明血小板COX-1活性特异性丧失，并提供了其对血小板功能和类二十烷代谢的影响。值得注意的是，尽管血小板没有形成血栓素A2，但尿中血栓素A2的代谢物在正常范围内，这表明这些不能被认为是体内血小板功能的标志。这项研究的结果是阿司匹林对血小板COX-1、血小板功能和类二十烷产生影响的重要基准，因为它们定义了人类选择性血小板COX-1消融。
We have identified a rare missense variant on chromosome 9, position 125145990 (GRCh37), in exon 8 in prostaglandin endoperoxide synthase 1 (PTGS1) (the gene encoding cyclo-oxygenase 1 [COX-1], the target of anti-thrombotic aspirin therapy). We report that in the homozygous state within a large consanguineous family this variant is associated with a bleeding phenotype and alterations in platelet reactivity and eicosanoid production. Western blotting and confocal imaging demonstrated that COX-1 was absent in the platelets of three family members homozygous for the PTGS1 variant but present in their leukocytes. Platelet reactivity, as assessed by aggregometry, lumi-aggregometry and flow cytometry, was impaired in homozygous family members, as were platelet adhesion and spreading. The productions of COXderived eicosanoids by stimulated platelets were greatly reduced but there were no changes in the levels of urinary metabolites of COX-derived eicosanoids. The proband exhibited additional defects in platelet aggregation and spreading which may explain why her bleeding phenotype was slightly more severe than those of other homozygous affected relatives. This is the first demonstration in humans of the specific loss of platelet COX-1 activity and provides insight into its consequences for platelet function and eicosanoid metabolism. Notably despite the absence of thromboxane A2 formation by platelets, urinary thromboxane A2 metabolites were in the normal range indicating these cannot be assumed as markers of in vivo platelet function. Results from this study are important benchmarks for the effects of aspirin upon platelet COX-1, platelet function and eicosanoid production as they define selective platelet COX-1 ablation within humans.
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DOI：
10.1083/jcb.200208043
发表时间：
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期刊：
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