THE WISKOTT-ALDRICH SYNDROME AND X-LINKED CONGENITAL THROMBOCYTOPENIA ARE CAUSED BY MUTATIONS OF THE SAME GENE
THE WISKOTT-ALDRICH SYNDROME AND X-LINKED CONGENITAL THROMBOCYTOPENIA ARE CAUSED BY MUTATIONS OF THE SAME GENE
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DOI：
10.1182/blood.v86.10.3797.bloodjournal86103797
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发表时间：
1995-11-15
期刊：
影响因子：
20.3
通讯作者：
OCHS, HD
中科院分区：
文献类型：
--
作者：
ZHU, QL;ZHANG, M;OCHS, HD
Wiskott-Aldrich综合征（WAS）是一种X连锁隐性遗传疾病，其特征为血小板减少症、小血小板、湿疹、复发性感染和免疫缺陷。除了经典的WAS表型，还有一组先天性X连锁血小板减少症（XLT）患者，他们的血小板很小，但只有短暂的湿疹，如果有的话，和最小的免疫缺陷。由于负责WAS的基因已经测序，因此有可能将WAS表型与WAS基因突变相关联。使用指纹筛选技术，我们确定了13个无关的WAS患者的轻微至严重的临床症状的突变的大致位置。从患者来源的细胞系获得的cDNA和基因组DNA的直接序列分析显示，整个WAS基因中分布有12个独特的突变，包括插入、缺失和导致氨基酸取代、终止、外显子跳跃或剪接缺陷的点突变。在4例不相关的XLT表型患者中，3例有影响外显子2的错义突变，1例有影响外显子9的剪接位点突变。经典WAS患者有更复杂的突变，导致终止密码子，移码和早期终止。这些发现提供了XLT和WAS是由同一基因突变引起的直接证据，并表明严重的临床表型与复杂的突变相关。(C)1995年，美国血液学会。
The Wiskott-Aldrich syndrome (WAS) is an X-linked recessive disorder characterized by thrombocytopenia, small platelets, eczema, recurrent infections, and immunodeficiency. Besides the classic WAS phenotype, there is a group of patients with congenital X-linked thrombocytopenia (XLT) who have small platelets but only transient eczema, if any, and minimal immune deficiency. Because the gene responsible for WAS has been sequenced, it was possible to correlate the WAS phenotypes with WAS gene mutations. Using a fingerprinting screening technique, we determined the approximate location of the mutation in 13 unrelated WAS patients with mild to severe clinical symptoms. Direct sequence analysis of cDNA and genomic DNA obtained from patient-derived cell lines showed 12 unique mutations distributed throughout the WAS gene, including insertions, deletions, and point mutations resulting in amino acid substitutions, termination, exon skipping, or splicing defects. Of 4 unrelated patients with the XLT phenotype, 3 had missense mutations affecting exon 2 and 1 had a splice-site mutation affecting exon 9. Patients with classic WAS had more complex mutations, resulting in termination codons, frameshift, and early termination. These findings provide direct evidence that XLT and WAS are caused by mutations of the same gene and suggest that severe clinical phenotypes are associated with complex mutations. (C) 1995 by The American Society of Hematology.