x -连锁γ球蛋白血症患者Bruton酪氨酸激酶基因5个新突变的分子和结构特征。
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Saha BK, Curtis SK, Vogler LB, Vihinen M
x -连锁γ球蛋白血症患者Bruton酪氨酸激酶基因5个新突变的分子和结构特征。
中华医学杂志1997 7月;3(7):477-85。
- PubMed ID
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9260159 (PubMed视图］
- 摘要
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背景:Btk(布鲁顿酪氨酸激酶)基因已被证明在人类免疫缺陷病XLA (x -连锁γ球蛋白血症)中发生突变。Btk是Tec家族细胞质蛋白酪氨酸激酶的成员，具有不同的功能域PH, TH, SH3, SH2和激酶。在XLA的每个Btk子域中都观察到突变。我们分析了来自5个不相关家族的6例XLA患者的Btk基因。材料与方法:从患者外周血中提取DNA。采用单链构象多态性(SSCP)技术对Btk外显子包括连接序列进行分析，pcr扩增后直接测序。对于结构分析，将错义突变引入到Btk的PH和激酶结构域的三维模型中，并根据蛋白质功能的知识预测结果。结果:鉴定出5个新的突变和2个新的多态性，均由单碱基改变引起。5个突变中有3个位于Btk的PH区，2个位于Btk的激酶区。其中3个突变为错义型，其中2个在PH域改变了相同的密码子; the third one was located in the kinase domain. The fourth mutation was a point deletion in the PH domain causing a frameshift followed by premature termination. The fifth mutation was a splice donor-site mutation within the kinase domain which could result in an exon skipping. In four of the five instances, mothers of the patients were shown to be obligate carriers. In one instance, a sibling sister was identified as a heterozygote establishing her as a carrier. CONCLUSIONS: Functional consequences of the mutations causing frameshifts and altered splicing can be inferred directly. Functional consequences of the missense mutations were interpreted by 3-dimensional structural modeling of Btk domains. It is proposed that the two PH domain mutations will interfere with membrane localization while the kinase domain mutation will interfere with the enzymatic function of Btk. This study provides further insight into the role of Btk in XLA.