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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity
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Mutations and common polymorphisms in ADAMTS13 gene responsible for von Willebrand factor-cleaving protease activity

机译：负责von Willebrand因子切割蛋白酶活性的ADAMTS13基因的突变和常见多态性

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摘要

Von Willebrand factor (VWF) is synthesized primarily in vascular endothelial cells and secreted into the plasma as unusually large VWF multimers. Normally, these multimers are quickly degraded into smaller forms by a plasma metalloproteinase, VWF-cleaving protease (VWF-CP). Decreases in the activity of this enzyme result in congenital and acquired thrombotic thrombocytopenic purpura (TIP). The human VWF-CP has recently been purified. Cloning of the corresponding cDNA revealed that the 1,427-aa polypeptide is a member of the ADAMTS gene family, termed ADAMTS13. Twelve rare mutations in this gene have been identified in patients with congenital TIP. Here, we report missense and nonsense mutations in two Japanese families with Upshaw-Schulman syndrome, congenital TTP with neonatal onset and frequent relapses. The comparison of individual ADAMTS13 genotypes and plasma VWF-CP activities indicated that the R268P, Q449stop, and C508Y mutations abrogated activity of the enzyme, whereas the P475S mutant retained low but significant activity. The effects of these mutations were further confirmed by expression analysis in HeLa cells. Re-combinant VWF-CP containing either the R268P or C508Y mutations was not secreted from cells. In contrast, Q449stop and P475S mutants were normally secreted but demonstrated minimal activity. Genotype analysis of 364 Japanese subjects revealed that P475S is heterozygous in 9.6% of individuals, suggesting that approximately 10% of the Japanese population possesses reduced VWF-CP activity. We report on a single-nucleotide polymorphism associated with alterations in VWF-CP activity; it will be important to assess this single-nucleotide polymorphism as a risk factor for thrombotic disorders.
机译：Von Willebrand因子（VWF）主要在血管内皮细胞中合成，并作为异常大的VWF多聚体分泌到血浆中。通常，这些多聚体通过血浆金属蛋白酶VWF裂解蛋白酶（VWF-CP）迅速降解成较小的形式。该酶活性的降低导致先天性和获得性血栓性血小板减少性紫癜（TIP）。人VWF-CP最近已被纯化。相应cDNA的克隆显示1,427-aa多肽是ADAMTS基因家族的一个成员，称为ADAMTS13。先天性TIP患者中已经鉴定出该基因的十二个罕见突变。在这里，我们报告了两个日本Upshaw-Schulman综合征，先天性TTP伴有新生儿发作和频繁复发的日本家庭的错义和无意义突变。单个ADAMTS13基因型和血浆VWF-CP活性的比较表明，R268P，Q449stop和C508Y突变废除了酶的活性，而P475S突变型保留了低而重要的活性。通过在HeLa细胞中进行表达分析，进一步证实了这些突变的作用。没有从细胞分泌出含有R268P或C508Y突变的重组VWF-CP。相反，通常会分泌Q449stop和P475S突变体，但显示出最小的活性。对364位日本受试者的基因型分析表明，P475S在9.6％的个体中是杂合的，这表明大约10％的日本人群的VWF-CP活性降低。我们报告了与VWF-CP活性改变相关的单核苷酸多态性；重要的是，评估这种单核苷酸多态性是血栓形成疾病的危险因素。

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