Analysis of DNA ligase IV mutations found in LIG4 syndrome patients:: the impact of two linked polymorphisms
Analysis of DNA ligase IV mutations found in LIG4 syndrome patients:: the impact of two linked polymorphisms
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DOI：
10.1093/hmg/ddh274
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发表时间：
2004-10-15
影响因子：
3.5
通讯作者：
Jeggo, PA
中科院分区：
文献类型：
--
作者：
Girard, PM;Kysela, B;Jeggo, PA
LIG4综合征患者在DNA连接酶IV中存在亚型突变。尽管五名确诊患者中有四名表现出免疫缺陷和发育迟缓，但一名患者发育正常。发育正常的患者有相同的纯合突变（R278H）的DNA连接酶IV作为一个更严重的影响患者，谁另外有两个连锁的多态性。在这里，我们研究了在LIG4综合征患者中鉴定的突变和多态性的影响。重组突变蛋白的检查表明，临床特征的严重程度与残余连接酶活性的水平相关。这些多态性使DNA连接酶IV的活性降低约2倍。当与其他轻度R278H突变结合时，活性降低到与其他表现出免疫缺陷和发育迟缓的LIG4患者相似的水平。这证明了突变和多态性的偶联如何对蛋白质功能产生显著影响，并提供了多态性可能影响临床结果的例子。对LIG4综合征（R580 X、R814 X和G469 E）中的其他突变变化的分析已经鉴定出DNA连接酶IV中的核定位信号和影响DNA连接酶IV腺苷酸化的位点。
LIG4 syndrome patients have hypomorphic mutations in DNA ligase IV. Although four of the five identified patients display immunodeficiency and developmental delay, one patient was developmentally normal. The developmentally normal patient had the same homozygous mutation (R278H) in DNA ligase IV as one of the more severely affected patients, who additionally had two linked polymorphisms. Here, we examine the impact of the mutations and polymorphisms identified in the LIG4 syndrome patients. Examination of recombinant mutant proteins shows that the severity of the clinical features correlates with the level of residual ligase activity. The polymorphisms decrease the activity of DNA ligase IV by similar to2-fold. When combined with the otherwise mild R278H mutation, the activity is reduced to a level similar to other LIG4 patients who display immunodeficiency and developmental delay. This demonstrates how coupling of a mutation and polymorphism can have a marked impact on protein function and provides an example where a polymorphism may have influenced clinical outcome. Analysis of additional mutational changes in LIG4 syndrome (R580X, R814X and G469E) have led to the identification of a nuclear localization signal in DNA ligase IV and sites impacting upon DNA ligase IV adenylation.