Prof. Dr. Barbara Zieger, University Medical Center Freiburg, Department of Pediatrics and Adolescent Medicine, Mathildenstr. 1, 79106 Freiburg, Germany, Tel.: +49 761 27043000, Fax: +49 761 27045820, E-mail:
Thromb Haemost. 2015 Apr;113(4):782-91. doi: 10.1160/TH14-05-0479. Epub 2014 Nov 6.
Glanzmann thrombasthenia (GT) is an autosomal recessive bleeding disorder characterised by quantitative and/or qualitative defects of the platelet glycoprotein (GP) IIb/IIIa complex, also called integrin αIIbβ3. αIIbβ3 is well known as a platelet fibrinogen receptor and mediates platelet aggregation, firm adhesion, and spreading. This study describes the molecular genetic analyses of 19 patients with GT who were diagnosed on the basis of clinical parameters and platelet analyses. The patients' bleeding signs include epistaxis, mucocutaneous bleeding, haematomas, petechiae, gastrointestinal bleeding, and menorrhagia. Homozygous or compound heterozygous mutations in ITGA2B or ITGB3 were identified as causing GT by sequencing of genomic DNA. All exons including exon/intron boundaries of both genes were analysed. In a patient with an intronic mutation, splicing of mRNA was analysed using reverse transcriptase (RT)-PCR of platelet-derived RNA. In short, 16 of 19 patients revealed 27 different mutations (ITGA2B: n=17, ITGB3: n=10). Seventeen of these mutations have not been published to date. Mutations in ITGA2B or ITGB3 were identified as causing GT in 16 patients. We detected a total of 27 mutations in ITGA2B and ITGB3 including 17 novel missense, nonsense, frameshift and splice site mutations. In addition, three patients revealed no molecular genetic anomalies in ITGA2B or ITGB3 that could explain the suspected diagnosis of GT. We assume that these patients may harbour defects in a regulatory element affecting the transcription of these genes, or other proteins may exist that are important for activating the αIIbβ3 complex that may be affected.
血管性假性血友病（GT）是一种常染色体隐性遗传性出血性疾病，其特征是血小板糖蛋白（GP）IIb/IIIa 复合物（也称为整合素 αIIbβ3）的数量和/或质量缺陷。αIIbβ3 是众所周知的血小板纤维蛋白原受体，介导血小板聚集、牢固黏附及伸展。本研究描述了 19 例 GT 患者的分子遗传学分析，这些患者是根据临床参数和血小板分析诊断的。患者的出血症状包括鼻出血、黏膜皮肤出血、血肿、瘀点、胃肠道出血和月经过多。通过对基因组 DNA 进行测序，确定 ITGA2B 或 ITGB3 的纯合子或复合杂合突变是导致 GT 的原因。分析了这两个基因的所有外显子，包括外显子/内含子边界。在具有内含子突变的患者中，通过血小板衍生 RNA 的逆转录酶（RT）-PCR 分析 mRNA 的剪接。简而言之，19 例患者中有 16 例发现了 27 种不同的突变（ITGA2B：n=17，ITGB3：n=10）。这些突变中有 17 种尚未发表。在 16 例患者中发现 ITGA2B 或 ITGB3 突变导致 GT。我们在 ITGA2B 和 ITGB3 中总共检测到 27 种突变，包括 17 种新的错义、无义、移码和剪接位点突变。此外，3 例患者在 ITGA2B 或 ITGB3 中未发现可解释 GT 可疑诊断的分子遗传异常。我们假设这些患者可能存在影响这些基因转录的调节元件缺陷，或者可能存在其他对激活对 αIIbβ3 复合物很重要的蛋白质。
