A second-site mutation in the initiation codon of WAS (WASP) results in expansion of subsets of lymphocytes in an Wiskott-Aldrich syndrome patient
A second-site mutation in the initiation codon of WAS (WASP) results in expansion of subsets of lymphocytes in an Wiskott-Aldrich syndrome patient
复制标题
DOI：
10.1002/humu.20308
复制
发表时间：
2006-04-01
期刊：
影响因子：
3.9
通讯作者：
Tsuchiya, S
中科院分区：
文献类型：
--
作者：
Du, W;Kumaki, S;Tsuchiya, S
Wiskott-Aldrich综合征（WAS）是由WAS蛋白（WASP）基因突变引起的。最近，在包括WAS在内的一些遗传性疾病中，有报道称由回复或第二位点突变引起的体细胞嵌合现象。在这篇文章中，我们描述了体细胞镶嵌在一个15岁的WAS患者由于二次击中突变的起始密码子。患者最初在WAS（WASP）基因中有一个单碱基缺失（c.11delG; p.G4fsX40），导致移码和废除蛋白质表达。随后，一部分T细胞和自然杀伤（NK）细胞表达了一种较小的WASP，它与其细胞伴侣WASP相互作用蛋白（WASP）结合。发现T和NIX细胞在起始密码子中具有另外的突变（c.1A > T，p.M1_P5del）。结果强烈表明，较小的WASP是从原始突变下游的第二个ATG翻译而来的，不仅T细胞，而且携带第二个突变的NK细胞也获得了比WASP阴性对应物更大的生长优势。据我们所知，这是第一个报告描述体细胞镶嵌由于第二个位点突变的起始密码子的任何遗传性疾病。
Wiskott-Aldrich syndrome (WAS) is caused by mutations in the gene encoding WAS protein (WASP). Recently, somatic mosaicism caused by reversions or second-site mutations has been reported in some inherited disorders including WAS. In this article, we describe somatic mosaicism in a 15,year-old WAS patient due to a second-hit mutation in the initiation codon. The patient originally had a single-base deletion (c.11delG; p.G4fsX40) in the WAS (WASP) gene, which resulted in a frameshift and abrogated protein expression. Subsequently, a fraction of T and natural killer (NK) cells expressed a smaller WASP, which binds to its cellular partner WASP, interacting protein (WIP). The T and NIX cells were found to have an additional mutation in the initiation codon (c.1A > T, p.M1_P5del). The results strongly suggest that the smaller WASP is translated from the second ATG downstream of the original mutation, and not only Tcells but also NK cells carrying the second mutation acquired a growth advantage over WASP negative counterparts. To our knowledge, this is the first report describing somatic mosaicism due to a second-site mutation in the initiation codon of any inherited disorders.