Centre for Stem Cell Research, Brown Foundation Institute of Molecular Medicine, University of Texas Health Science Center, Houston, TX, USA.
Clin Immunol. 2010 Apr;135(1):72-83. doi: 10.1016/j.clim.2009.12.011. Epub 2010 Feb 2.
The reasons underlying the occurrence of multiple revertant genotypes in Wiskott-Aldrich syndrome (WAS) patients remain unclear. We have identified more than 30 revertant genotypes in a C995T WAS patient having 10-15% revertant, WAS protein (WASp)-expressing circulating lymphocytes. Of 497 allospecific T-cell clones generated from the peripheral blood, 47.1% carried a revertant sequence. All revertant T-cell clones exhibited restoration of WASp expression. However, anti-CD3-induced proliferative responses varied greatly amongst revertants. Several revertant T-cell clones expressed an internally deleted WASp mutant lacking much of the proline-rich region. This potentially accounts for the reduced anti-CD3 proliferative responses of these T-cell clones. We found no evidence for an increased DNA mutation rate in this patient. We conclude that the diversity of revertant genotypes in our patient does not result from an extraordinary mutation rate and that the amino acid sequence space explored by WASp in revertant T-cells is significantly smaller than might have been predicted from the diversity of revertant genotypes.
导致威特综合征（Wiskott-Aldrich syndrome，WAS）患者中出现多种回复突变基因型的原因尚不清楚。我们在一位 C995T WAS 患者中发现了超过 30 种回复突变基因型，该患者有 10-15%的回复突变，表达 WAS 蛋白（WASp）的循环淋巴细胞。从外周血中生成的 497 个同种异体 T 细胞克隆中，有 47.1%携带回复突变序列。所有回复突变 T 细胞克隆均表现出 WASp 表达的恢复。然而，抗 CD3 诱导的增殖反应在回复突变体之间差异很大。一些回复突变 T 细胞克隆表达了一种内部缺失的 WASp 突变体，缺乏富含脯氨酸的区域的大部分。这可能解释了这些 T 细胞克隆抗 CD3 增殖反应降低的原因。我们在该患者中未发现 DNA 突变率增加的证据。我们得出结论，我们患者中的回复突变基因型的多样性不是由于异常高的突变率造成的，而且在回复突变 T 细胞中，WASp 探索的氨基酸序列空间明显小于从回复突变基因型的多样性中可能预测到的范围。
