A single F153Sβ3 mutation causes constitutive integrin αIIbβ3 activation in a variant form of Glanzmann thrombasthenia.
A single F153Sβ3 mutation causes constitutive integrin αIIbβ3 activation in a variant form of Glanzmann thrombasthenia.
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单个F153Sβ3突变导致本构成素αIIBβ3激活以一种变异形式的Glanzmann血栓症。
DOI：
10.1182/bloodadvances.2022009495
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发表时间：
2023-07-11
期刊：
影响因子：
7.5
通讯作者：
Wilcox, David A.
中科院分区：
文献类型：
--
作者：
Koukouritaki, Sevasti B.;Thinn, Aye Myat M.;Ashworth, Katrina J.;Fang, Juan;Slater, Haley S.;Du, Lily M.;Nguyen, Huong Thi Thu;Pillois, Xavier;Nurden, Alan T.;Ng, Christopher J.;Di Paola, Jorge;Zhu, Jieqing;Wilcox, David A.
Glanzmann血栓性血小板保留止血功能，仅低水平表达α IIb-F153 S β3的组成型活性突变形式。F153β3氨基酸的大体积芳香族非极性结构对于正常αIIbβ3整联蛋白从静息状态转变为活化状态至关重要。本报告确定了一种新的变异形式的遗传性出血性疾病Glanzmann血小板无力症，表现出只有轻度出血的身体活动的个人。血小板不能用生理性活化激动剂离体聚集，尽管用全血进行的微流体分析显示出与轻度出血一致的中度离体血小板粘附和聚集。免疫细胞计数显示，自发结合/储存纤维蛋白原的静止血小板上αIIbβ3的表达减少，活化依赖性抗体（配体诱导结合位点-319.4和PAC-1）报告β3延伸，提示内在活化表型。遗传分析显示，ITGB 3外显子4的杂合T556 C核苷酸取代导致β I结构域内的单个F153 S β3取代，以及先前报告的IVS 5（+1）G>A剪接位点突变，无法检测到血小板信使RNA，导致S153β3半合子表达。F153在几个物种的β3和所有人β-整联蛋白亚基中是完全保守的，这表明它可能在整联蛋白结构/功能中起重要作用。α IIb-F153 S β3的突变也显示HEK 293 T细胞上组成型活化的αIIb-S153β3水平降低。整体结构分析表明，大体积芳香族非极性氨基酸（F，W）153β3对于维持β I结构域的α2-和α1-螺旋的静息构象至关重要，因为小的氨基酸取代（S，A）促进β I结构域的α2-和α1-螺旋向组成性活性αIIbβ3构象的不受阻碍的向内移动，而大体积芳香族，极性氨基酸（Y）阻碍这种运动并抑制αIIbβ3活化。这些数据共同表明，F153β3的破坏可以显著改变正常的整合素/血小板功能，尽管α IIb-S153 β3表达的降低可能通过促进有效止血的过度活性构象来补偿。
Glanzmann thrombasthenic platelets retain hemostatic function with only low-level expression of a constitutively active mutant form of αIIb-F153Sβ3. The bulky aromatic, nonpolar structure of F153β3 amino acid is vital for normal αIIbβ3 integrin shift from resting to an activated state. This report identifies a novel variant form of the inherited bleeding disorder Glanzmann thrombasthenia, exhibiting only mild bleeding in a physically active individual. The platelets cannot aggregate ex vivo with physiologic agonists of activation, although microfluidic analysis with whole blood displays moderate ex vivo platelet adhesion and aggregation consistent with mild bleeding. Immunocytometry shows reduced expression of αIIbβ3 on quiescent platelets that spontaneously bind/store fibrinogen, and activation-dependent antibodies (ligand-induced binding site–319.4 and PAC-1) report β3 extension suggesting an intrinsic activation phenotype. Genetic analysis reveals a single F153Sβ3 substitution within the βI-domain from a heterozygous T556C nucleotide substitution of ITGB3 exon 4 in conjunction with a previously reported IVS5(+1)G>A splice site mutation with undetectable platelet messenger RNA accounting for hemizygous expression of S153β3. F153 is completely conserved among β3 of several species and all human β-integrin subunits suggesting that it may play a vital role in integrin structure/function. Mutagenesis of αIIb-F153Sβ3 also displays reduced levels of a constitutively activated αIIb-S153β3 on HEK293T cells. The overall structural analysis suggests that a bulky aromatic, nonpolar amino acid (F,W)153β3 is critical for maintaining the resting conformation of α2- and α1-helices of the βI-domain because small amino acid substitutions (S,A) facilitate an unhindered inward movement of the α2- and α1-helices of the βI-domain toward the constitutively active αIIbβ3 conformation, while a bulky aromatic, polar amino acid (Y) hinders such movements and restrains αIIbβ3 activation. The data collectively demonstrate that disruption of F153β3 can significantly alter normal integrin/platelet function, although reduced expression of αIIb-S153β3 may be compensated by a hyperactive conformation that promotes viable hemostasis.
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影响因子：
4.8
作者：
Schaffner-Reckinger, E;Gouon, V;Kieffer, N
通讯作者：
Kieffer, N
DOI：
10.1073/pnas.1422238112
发表时间：
2015-04-14
影响因子：
11.1
作者：
Buitrago, Lorena;Rendon, Augusto;Coller, Barry S.
通讯作者：
Coller, Barry S.
影响因子：
2
作者：
Nurden A
通讯作者：
Nurden A
影响因子：
7.5
作者：
Ross, Justyne E.;Zhang, Bing M.;Di Paola, Jorge
通讯作者：
Di Paola, Jorge
影响因子：
10.4
作者：
Fang, J.;Nurden, P.;Wilcox, D. A.
通讯作者：
Wilcox, D. A.