Jiang Hong, Tang Beisha, Xia Kun, Hu Zhengmao, Shen Lu, Tang Jianguang, Zhao Guohua, Zhang Yuhu, Cai Fang, Pan Qian, Long Zhigao, Wang Guo, Dai Heping
Department of Neurology, Xiangya Hospital, Central South University, Changsha, Hunan 410008, PR China.
J Neurol Sci. 2006 Feb 15;241(1-2):1-6. doi: 10.1016/j.jns.2005.09.001. Epub 2005 Dec 27.
Ataxia telangiectasia (A-T) is an autosomal recessive disorder characterized by cerebellar ataxia, telangiectasia, immunodeficiency, elevated alpha-fetoprotein level, chromosomal instability, predisposition to cancer, and radiation sensitivity. Although a lot of mutations in the ATM gene have been described, there is still no report about ATM mutations in Chinese population. Using a molecular approach, we screened for ATM mutations in two patients from two unrelated Chinese families. 100 normal controls were analyzed to exclude possibility of polymorphism. Two novel mutations in the ATM gene were identified. The first one is a novel, homozygous, 1346G>C (Gly449Ala) missense mutation. The second one is a compound heterozygous mutation, which consists of a novel, 610G>T (Gly204Stop) nonsense mutation, combined with a previously reported, 6679C>T (Arg2227Cys) missense mutation. The transversions 1346G>C (Gly449Ala) and 610G>T (Gly204Stop) are not localized either in the conserved PI-3 kinase domain or in the other domains of the ATM protein. The phenotypic features were characterized by progressive cerebellar ataxia, ocular telangiectasia, elevated alpha-fetoprotein level, immunodeficiency (agammaglo-bulinemia and T-cell defect), and rearrangements of chromosomes 7 and 14; brain MRI showed cerebellar atrophy, brain SPECT showed cerebellar regional cerebral blood flow (rCBF) hypoperfusion. To our knowledge, this is the first report of ATM mutations in Mainland China, in which the transversions 1346G>C (Gly449Ala) and 610G>T (Gly204Stop) are two novel, disease-causing mutations.
共济失调毛细血管扩张症（A-T）是一种常染色体隐性疾病，其特征为小脑共济失调、毛细血管扩张、免疫缺陷、甲胎蛋白水平升高、染色体不稳定、易患癌症以及对辐射敏感。尽管已报道了许多ATM基因的突变，但中国人群中ATM基因突变的报道仍未出现。我们采用分子方法，对来自两个不相关中国家庭的两名患者进行了ATM基因突变筛查。对100名正常对照进行分析以排除多态性的可能性。我们鉴定出了ATM基因的两个新突变。第一个是新的纯合1346G>C（甘氨酸449变为丙氨酸）错义突变。第二个是复合杂合突变，由一个新的610G>T（甘氨酸204变为终止密码子）无义突变与先前报道的6679C>T（精氨酸2227变为半胱氨酸）错义突变组成。1346G>C（甘氨酸449变为丙氨酸）和610G>T（甘氨酸204变为终止密码子）的颠换既不在保守的PI-3激酶结构域，也不在ATM蛋白的其他结构域中。其表型特征为进行性小脑共济失调、眼部毛细血管扩张、甲胎蛋白水平升高、免疫缺陷（无丙种球蛋白血症和T细胞缺陷）以及7号和14号染色体重排；脑部MRI显示小脑萎缩，脑SPECT显示小脑区域脑血流量（rCBF）灌注不足。据我们所知，这是中国大陆关于ATM基因突变的首次报道，其中1346G>C（甘氨酸449变为丙氨酸）和610G>T（甘氨酸204变为终止密码子）的颠换是两个新的致病突变。
