Identification of a novel nuclear localization signal in Tbx1 that is deleted in DiGeorge syndrome patients harboring the 1223delC mutation
Identification of a novel nuclear localization signal in Tbx1 that is deleted in DiGeorge syndrome patients harboring the 1223delC mutation
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DOI：
10.1093/hmg/ddi081
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发表时间：
2005-04-01
影响因子：
3.5
通讯作者：
Epstein, JA
中科院分区：
文献类型：
--
作者：
Stoller, JZ;Epstein, JA
DiGeorge综合征(DGS)是人类最常见的染色体缺失综合征，常与22q11号染色体缺失有关。大约17%具有这种综合征表型特征的患者没有可检测到的基因组缺失。利用小鼠模型进行的动物研究表明，TBX1是常见缺失区的关键基因，最近在非缺失患者中发现了几个突变，包括错义突变和移码突变。这些突变导致疾病的机制尚不清楚。我们已经在TBX1的C末端发现了一个先前未被识别的新的核定位信号(NLS)，该信号被1223delC突变缺失，从而解释了这些患者的疾病机制。这种NLS在包括brachyury和Tbx10在内的T-box蛋白亚家族中以及在其他核蛋白中都是保守的。通过提供功能数据来表明1223delC TBX1突变导致的功能丧失，我们的结果为TBX1突变可导致人类DGS的结论提供了强有力的支持。
DiGeorge syndrome (DGS) is the most common human chromosomal deletion syndrome and is frequently associated with deletions on chromosome 22q11. Approximately 17% of patients with the phenotypic features of this syndrome have no detectable genomic deletion. Animal studies using mouse models have implicated Tbx1 as a critical gene within the commonly deleted region, and several mutations in TBX1 have been identified recently in non-deleted patients, including missense and frameshift mutations. The mechanisms by which these mutations cause disease have remained unclear. We have identified a previously unrecognized and novel nuclear localization signal (NLS) at the C-terminus of Tbx1 that is deleted by the 1223delC mutation, thus explaining the mechanism of disease in these patients. This NLS is conserved across species, among a subfamily of T-box proteins including Brachyury and Tbx10, and among additional nuclear proteins. By providing functional data to indicate loss-of-function produced by the 1223delC TBX1 mutation, our results provide strong support for the conclusion that TBX1 mutations can cause DGS in humans.