Wiskott-Aldrich syndrome/X-linked thrombocytopenia in China: Clinical characteristic and genotype-phenotype correlation
Wiskott-Aldrich syndrome/X-linked thrombocytopenia in China: Clinical characteristic and genotype-phenotype correlation
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DOI：
10.1002/pbc.25559
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发表时间：
2015-09-01
影响因子：
3.2
通讯作者：
Zhao, Xiao-Dong
中科院分区：
文献类型：
--
作者：
Liu, Da-Wei;Zhang, Zhi-Yong;Zhao, Xiao-Dong
研究背景Wiskott-Aldrich综合征（WAS）和X连锁血小板减少症（XLT）是由WAS基因突变引起的。WAS和XLT的基因型-表型关联尚未完全阐明。我们收集了81例WAS/XLT患者的临床资料，从基因组DNA水平和转录/翻译水平分析了WAS基因突变，并通过流式细胞术定量PBMCs中WAS蛋白（WASp）表达的三种不同模式。包括20个新的突变和8个热点，来自75个无关的家庭，共81名受影响的成员。几乎所有的XLT患者都有错义突变，并且在外周细胞中呈WASp阳性，而只有一半的错义突变患者表现出XLT表型和可检测到的WASp。相反，无义突变、缺失、插入和复杂突变的患者为WASP阴性，并发展为经典的WAS表型。相同数量的剪接异常患者WASP阳性或WASP阴性。WASP阴性患者的长期生存率较低WASP阳性patients.ConclusionsThe经典WAS或轻度XLT和长期结果的临床表型可能会影响这些缺陷对基因转录和翻译的影响。具有允许表达突变的WASp的错义突变的患者和具有剪接异常的患者（其导致产生多种产物，包括正常的WASp）呈现减弱的XLT表型并显示出更好的预后。儿科血液癌症2015;62：1601-1608。(c)2015 Wiley Periodicals，Inc.
BackgroundWiskott-Aldrich syndrome (WAS) and X-linked thrombocytopenia (XLT) are caused by mutations of the WAS gene. The genotype-phenotype association of WAS and XLT have not been fully elucidated. Here, we established the largest database of WAS in China to further determine the potential correlation between genotype and phenotype and long-term outcome.ProceduresWe collected clinical data of 81 WAS/XLT patients, analyzed mutations of WAS gene at the genomic DNA and transcriptional/translational levels, and quantified three different patterns of WAS protein (WASp) expression in PBMCs by flow cytometry.ResultsThere were 60 unique mutations identified, including 20 novel mutations and eight hotspots, from 75 unrelated families with a total of 81 affected members. Nearly all the patients with XLT had missense mutations and were WASp-positive in the peripheral cells, while only half of the patients with missense mutations exhibited the XLT phenotype and detectable WASp. In contrast, patients with nonsense mutations, deletions, insertions, and complex mutations were WASp-negative and developed the classic WAS phenotype. An equal number of patients with splice anomalies were either WASp-positive or WASp-negative. Long-term survival rates were lower in WASp-negative patients compared to WASp-positive patients.ConclusionsThe clinical phenotype of classic WAS or milder XLT and long-term outcome are potentially influenced by the effect of these defects on gene transcription and translation. Patients with missense mutations allowing expression of mutated WASp and those with splice anomalies, which result in generation of multiple products, including normal WASp, present the attenuated XLT phenotype and show better prognosis. Pediatr Blood Cancer 2015;62:1601-1608. (c) 2015 Wiley Periodicals, Inc.