Derry J M, Kerns J A, Weinberg K I, Ochs H D, Volpini V, Estivill X, Walker A P, Francke U
Howard Hughes Medical Institute, Stanford University Medical Center, CA 94305, USA.
Hum Mol Genet. 1995 Jul;4(7):1127-35. doi: 10.1093/hmg/4.7.1127.
The WASP gene has been recently cloned from Xp11.23 and shown to be mutated in three patients with the Wiskott-Aldrich syndrome (WAS). We have developed a screening protocol for identifying WASP gene alterations in genomic DNA and have identified a spectrum of novel mutations in 12 additional unrelated families. These missense, nonsense and frameshift mutations involve eight of the 12 exons of the gene. Two mutations creating premature termination codons were associated with lack of detectable mRNA on Northern blots. Four amino acid substitutions, Leu27Phe, Thr48Ile, Val75Met and Arg477Lys, were found in patients with congenital thrombocytopenia and no clinically evident immune defect indicating that the WASP gene is the site for mutations in X-linked thrombocytopenia as well as in WAS. A T-cell line from a WAS patient contained two independent DNA alterations, a constitutional frameshift mutation, also present in peripheral blood leukocytes from the patient, and compensatory splice site mutation unique to the cell line. The distribution of eight missense mutations provides valuable information on amino acids which are essential for normal protein function, and suggests that sites in the first two exons are hot-spots for mutation.
WASP基因最近已从Xp11.23克隆出来，并在3例Wiskott-Aldrich综合征（WAS）患者中发现发生了突变。我们已开发出一种筛选方案，用于鉴定基因组DNA中的WASP基因改变，并在另外12个无亲缘关系的家族中鉴定出一系列新的突变。这些错义、无义及移码突变涉及该基因12个外显子中的8个。两个产生提前终止密码子的突变与Northern印迹上未检测到mRNA相关。在先天性血小板减少症且无明显临床免疫缺陷的患者中发现了4个氨基酸替代，即Leu27Phe、Thr48Ile、Val75Met和Arg477Lys，这表明WASP基因是X连锁血小板减少症以及WAS中突变的位点。来自一名WAS患者的T细胞系含有两个独立的DNA改变，一个是构成性移码突变，也存在于该患者的外周血白细胞中，另一个是该细胞系特有的补偿性剪接位点突变。8个错义突变的分布为正常蛋白质功能所必需的氨基酸提供了有价值的信息，并表明前两个外显子中的位点是突变热点。
