Genetic deletion of mouse platelet glycoprotein Ibβ produces a Bernard-Soulier phenotype with increased α-granule size
Genetic deletion of mouse platelet glycoprotein Ibβ produces a Bernard-Soulier phenotype with increased α-granule size
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DOI：
10.1182/blood-2004-03-1127
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发表时间：
2004-10-15
期刊：
影响因子：
20.3
通讯作者：
Ware, J
中科院分区：
文献类型：
--
作者：
Kato, K;Martinez, C;Ware, J
在这里，我们报告的Bernard-Soulier综合征的小鼠模型产生的有针对性的破坏基因编码的糖蛋白（GP）Ibbeta亚基的GP Ib-IX复合物的表征。与通过破坏小鼠GP Ibalpha亚基产生的Bernard-Soulier模型相似，GP Ibbeta（BMPs）小鼠显示出巨血小板减少症和严重出血表型。当通过透射电子显微镜检查时，与来自对照小鼠血小板的α-颗粒相比，由GP Ib β（IIb）基因型产生的大血小板显示具有增加的尺寸的α-颗粒。提供了将septin蛋白SEPT 5的过表达与GIP Ibbeta（GIP）血小板中存在较大α-颗粒联系起来的数据。SEPT 5基因位于GP Ibbeta基因5'端约250个核苷酸处，并且作为突触前蛋白复合物的一部分与调节来自神经元和血小板的胞吐作用相关。存在于巨核细胞中的融合mRNA转录物可含有SEPT 5和GP Ib β编码序列两者，从而在人和小鼠SEPT 5基因的3'端内产生不完全的多聚腺苷酸化信号。我们观察到GP Ibbeta（PIB）小鼠血小板中SEPT 5蛋白水平增加2至3倍。这些结果暗示SEPT 5水平在维持正常的α颗粒大小，并可能解释与人类GP Ib β突变和Bernard-Soulier综合征相关的变异颗粒。(C)2004年，美国血液学会。
Here we report the characterization of a mouse model of the Bernard-Soulier syndrome generated by a targeted disruption of the gene encoding the glycoprotein (GP) Ibbeta subunit of the GP Ib-IX complex. Similar to a Bernard-Soulier model generated by disruption of the mouse GP Ibalpha subunit, GP Ibbeta(Null) mice display macro-thrombocytopenia and a severe bleeding phenotype. When examined by transmission electron microscopy, the large platelets produced by a GP Ibbeta(Null) genotype revealed a-granules with increased size as compared with the alpha-granules from control mouse platelets. Data are presented linking the overexpression of a septin protein, SEPT5, to the presence of larger a-granules in the GIP Ibbeta(Null) platelet. The SEPT5 gene resides approximately 250 nucleotides 5' to the GP Ibbeta gene and has been associated with modulating exocytosis from neurons and platelets as part of a presynaptic protein complex. Fusion mRNA transcripts present in megakaryocytes can contain both the SEPT5 and GP Ibbeta coding sequences as a result in an imperfect polyadenylation signal within the 3' end of both the human and mouse SEPT5 genes. We observed a 2- to 3-fold increase in SEPT5 protein levels in platelets from GP Ibbeta(Null) mice. These results implicate SEPT5 levels in the maintenance of normal alpha-granule size and may explain the variant granules associated with human GP Ibbeta mutations and the Bernard-Soulier syndrome. (C) 2004 by The American Society of Hematology.