Predominance of null mutations in ataxia-telangiectasia
Predominance of null mutations in ataxia-telangiectasia
复制标题
DOI：
10.1093/hmg/5.4.433
复制
发表时间：
1996-04-01
影响因子：
3.5
通讯作者：
BarShira, A
中科院分区：
文献类型：
--
作者：
Gilad, S;Khosravi, R;BarShira, A
共济失调毛细血管扩张症（A-T）是一种常染色体隐性遗传疾病，涉及小脑变性、免疫缺陷、染色体不稳定、放射敏感性和癌症易感性。最近通过定位克隆鉴定了相关基因 AIM，并发现它编码一种推定的 350 kDa 蛋白质，具有 PI 3 激酶样结构域，可能参与介导响应辐射诱导的 DNA 损伤的细胞周期停滞。 A-T 突变的性质和位置应该有助于深入了解 ATM 蛋白的功能和这种多效性疾病的分子基础。迄今为止，在我们鉴定的 44 个 A-T 突变中，有 39 个 (89%) 预计会通过截短 ATM 蛋白、取消正确的翻译起始或终止或删除大片段来使其失活。其他突变包括 4 个较小的框内缺失和插入，以及 PI 3 激酶结构域中高度保守氨基酸的 1 个取代。因此，引起 A-T 的新兴突变主要是那些预计会完全失活 AIM 蛋白的突变。影响较轻的 ATM 突变可能会导致与 A-T 相关但不相同的表型。
Ataxia-telangiectasia (A-T) is an autosomal recessive disorder involving cerebellar degeneration, immunodeficiency, chromosomal instability, radiosensitivity and cancer predisposition. The responsible gene, AIM, was recently identified by positional cloning and found to encode a putative 350 kDa protein with a PI 3-kinase-like domain, presumably involved in mediating cell cycle arrest in response to radiation-induced DNA damage. The nature and location of A-T mutations should provide insight into the function of the ATM protein and the molecular basis of this pleiotropic disease. Of 44 A-T mutations identified by us to date, 39 (89%) are expected to inactivate the ATM protein by truncating it, by abolishing correct initiation or termination of translation, or by deleting large segments. Additional mutations are four smaller in-frame deletions and insertions, and one substitution of a highly conserved amino acid at the PI 3-kinase domain. The emerging profile of mutations causing A-T is thus dominated by those expected to completely inactivate the AIM protein. ATM mutations with milder effects may result in phenotypes related, but not identical, to A-T.