van Belzen M J, Hiel J A, Weemaes C M, Gabreëls F J, van Engelen B G, Smeets D F, van den Heuvel L P
Laboratory of Pediatrics and Neurology, University Hospital Nijmegen, The Netherlands.
Hum Genet. 1998 Feb;102(2):187-91. doi: 10.1007/s004390050675.
Ataxia telangiectasia (AT) is an autosomal recessive disorder characterized by cerebellar ataxia, telangiectasia, immunodeficiency, elevated alpha-fetoprotein levels, chromosomal instability, predisposition to cancer, and radiation sensitivity. We report the identification of a new, double missense mutation in the ataxia telangiectasia gene (ATM) of a Dutch family. This homozygous mutation consists of two consecutive base substitutions in exon 55: a T-->G transversion at position 7875 of the ATM cDNA and a G-->C transversion at position 7876. These transversions were confirmed by polymerase chain reaction/primer-induced restriction analysis with CelII. The double base substitution results in an amino acid change of an aspartic acid to a glutamic acid at codon 2625 and of an alanine to a proline at codon 2626 of the ATM protein. Both amino acids are conserved between the ATM protein and its functional homolog, the Atm gene product in the mouse. Furthermore, the Chou-Fasman and Robson predictions both demonstrate a change in the secondary structure of the ATM protein carrying the D2625E/A2626P mutation. These findings suggest that the double base substitution in the ATM gene is a disease-causing mutation.
共济失调毛细血管扩张症（AT）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。我们报告了在一个荷兰家庭的共济失调毛细血管扩张症基因（ATM）中鉴定出一种新的双错义突变。这种纯合突变由外显子55中的两个连续碱基替换组成：ATM cDNA第7875位的T→G颠换和第7876位的G→C颠换。这些颠换通过使用CelII的聚合酶链反应/引物诱导限制性分析得以证实。双碱基替换导致ATM蛋白第2625密码子处的天冬氨酸变为谷氨酸，以及第2626密码子处的丙氨酸变为脯氨酸。这两种氨基酸在ATM蛋白与其功能同源物——小鼠中的Atm基因产物之间是保守的。此外，Chou-Fasman和Robson预测均表明携带D2625E/A2626P突变的ATM蛋白二级结构发生了变化。这些发现表明ATM基因中的双碱基替换是一种致病突变。
