Characterization of ATM gene mutations in 66 ataxia telangiectasia families
Characterization of ATM gene mutations in 66 ataxia telangiectasia families
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DOI：
10.1093/hmg/8.1.69
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发表时间：
1999-01-01
影响因子：
3.5
通讯作者：
Schindler, D
中科院分区：
文献类型：
--
作者：
Sandoval, N;Platzer, M;Schindler, D
共济失调毛细血管扩张症（AT）是一种常染色体隐性遗传病，以神经和免疫症状、放射敏感性和癌症易感性为特征。在AT中突变的基因，被称为ATM基因，编码一个具有PI-3激酶相关结构域的大蛋白激酶。在这项研究中，我们调查了居住在德国的AT患者队列中ATM基因的突变谱。我们从66例无亲缘关系AT患者的基因组DNA中扩增并测序了所有66个外显子和侧翼非翻译区。我们鉴定了46个不同的ATM突变和26个序列多态性和变异分散在整个基因中。在其他人群中，共有34个突变未被发现。七个突变发生在不止一个家庭中，但在我们的患者组中，这些突变都不超过五个等位基因。大多数突变是截断的，证实了全长ATM蛋白的缺失是AT最常见的分子基础。转录分析表明，单外显子跳变是大多数剪接位点替换的结果，但在两个突变中观察到更复杂的模式。对携带ATM错义替换或框内缺失的细胞系进行免疫印迹研究，在四种情况下检测到残留的ATM蛋白。其中一种突变是靠近激酶结构域的缬氨酸缺失，导致AT淋巴母细胞样细胞系中ATM蛋白水平降至正常水平的20%。总之，我们的研究结果调查并描述了通过外显子扫描测序鉴定的ATM基因的大量变异，并表明在非孤立人群中引起AT的突变具有高度多样性。
Ataxia telangiectasia (AT) is an autosomal recessive disease characterized by neurological and immunological symptoms, radiosensitivity and cancer predisposition. The gene mutated in AT, designated the ATM gene, encodes a large protein kinase with a PI-3 kinase-related domain. In this study, we investigated the mutational spectrum of the ATM gene in a cohort of AT patients living in Germany. We amplified and sequenced all 66 exons and the flanking untranslated regions from genomic DNA of 66 unrelated AT patients. We identified 46 different ATM mutations and 26 sequence polymorphisms and variants scattered throughout the gene. A total of 34 mutations have not been described in other populations. Seven mutations occurred in more than one family, but none of these accounted for more than five alleles in our patient group. The majority of the mutations were truncating, confirming that the absence of full-length ATM protein is the most common molecular basis of AT, Transcript analyses demonstrated single exon skipping as the consequence of most splice site substitutions, but a more complex pattern was observed for two mutations. Immunoblot studies of cell lines carrying ATM missense substitutions or in-frame deletions detected residual ATM protein in four cases. One of these mutations, a valine deletion proximal to the kinase domain, resulted in ATM protein levels >20% of normal in an AT lymphoblastoid cell line. In summary, our results survey and characterize a plethora of variations in the ATM gene identified by exon scanning sequencing and indicate a high diversity of mutations giving rise to AT in a non-isolated population.