Molecular defects in ITGA2B and ITGB3 genes in patients with Glanzmann thrombasthenia
Molecular defects in ITGA2B and ITGB3 genes in patients with Glanzmann thrombasthenia
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DOI：
10.1111/j.1538-7836.2009.03579.x
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发表时间：
2009-11-01
影响因子：
10.4
通讯作者：
Saxena, R.
中科院分区：
文献类型：
--
作者：
Kannan, M.;Ahmad, F.;Saxena, R.
背景：格兰茨曼血小板无力症（GT）是一种常染色体隐性遗传性血小板功能缺陷，其特征是多种生理激动剂引起的血小板聚集减少或缺乏。该缺陷是由编码 ITGA2B 或 ITGB3 的基因突变引起的。这会导致血小板受体 α IIb-β 3 的定性或定量异常。 目的：本研究的目的是鉴定 GT 患者的突变并将其与患者表型相关联。对象和方法：总共 45 名不相关的 GT 患者参加了本研究，以确定致病分子缺陷，并将他们的表型与基因型相关联。对所有患者进行血小板聚集、流式细胞术、蛋白质印迹、构象敏感凝胶电泳（CSGE）突变筛查以及测序。分析了各个家族中新突变的外显率。结果：在 45 名不相关的 GT 患者中总共鉴定出 22 个新突变。 45 名患者中的 36 名 (80%) 发现了突变。大多数 GT 患者 (59%) 都发现了错义突变。其余的突变是异质的，分布在整个基因的长度上。对家庭成员的分析显示所有家庭均存在杂合突变。结论：重度 I 型 GT 是本研究中最常见的亚型。错义突变被确定为大多数 GT 患者的缺陷。这些家庭中的携带者检测和遗传咨询是减轻严重型 GT 负担的潜在有效替代方案。
Background: Glanzmann thrombasthenia (GT) is an autosomal recessive inherited platelet function defect that is characterized by reduction in, or absence of, platelet aggregation in response to multiple physiologic agonists. The defect is caused by mutations in the genes encoding ITGA2B or ITGB3. This results in qualitative or quantitative abnormalities of the platelet receptor, alpha IIb-beta 3. Objectives: The aim of this study was to identify the mutations in GT patients and to correlate these with patient phenotype. Subjects and methods: A total of 45 unrelated patients with GT were enrolled in the present study to identify the causative molecular defects, and also to correlate their phenotype with their genotype. Platelet aggregation, flow cytometry, Western blotting, and mutation screening by conformation sensitive gel electrophoresis (CSGE) followed by sequencing were performed in all patients. Novel mutations were analyzed for penetrance in individual families. Results: A total of 22 novel mutations were identified in 45 unrelated GT patients. Mutations were identified in 36 of the 45 (80%) patients. Missense mutations were seen in most of the GT patients (59%). The remaining mutations were heterogeneous and were distributed throughout the length of the gene. Analysis of family members showed heterozygous mutations in all families. Conclusions: The severe type I GT was the most common subtype found in this study. Missense mutations were identified as the defects responsible for most GT patients. Carrier detection and genetic counseling in these families is a potentially effective alternative for decreasing the burden of severe type of GT.