Genotype-phenotype relationships in ataxia-telangiectasia and variants
Genotype-phenotype relationships in ataxia-telangiectasia and variants
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DOI：
10.1086/301755
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发表时间：
1998-03-01
影响因子：
9.8
通讯作者：
Bar-Shira, A
中科院分区：
文献类型：
--
作者：
Gilad, S;Chessa, L;Bar-Shira, 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，其特征是小脑变性、免疫缺陷、染色体不稳定、放射敏感性和癌症易感性。A-T细胞对电离辐射和拟辐射化学物质敏感，并且在用这些试剂处理后不能激活细胞周期检查点。负责的基因ATM编码具有磷脂酰肌醇3-激酶样结构域的大蛋白激酶。在大多数情况下，典型的A-T表型是由截断或严重破坏ATM蛋白的无效ATM等位基因引起的。罕见的患者有较轻的临床表现或细胞特征的疾病已被报告，并已被指定为“A-T变异。AT的一种特殊变体是A-T-Fresno，它结合了典型的A-T表型与小头畸形和智力迟钝。这些综合征与ATM的可能关联对于理解其分子基础以及咨询和诊断目的都很重要。我们定量了六种A-T变体中的ATM蛋白水平，并搜索了它们的ATM基因突变。来自这些患者的细胞系在放射敏感性方面表现出相当大的变异性，同时显示出A-T细胞的典型放射抗性DNA合成。与经典的A-T患者不同，这些患者的ATM水平为正常水平的1%-17%。潜在的ATM基因型是预期产生轻度表型的突变的纯合子或轻度和重度突变的复合杂合子。A-（弗雷斯诺）细胞系被发现缺乏ATM蛋白和纯合子的严重ATM突变。我们的结论是，某些“A-T变异”表型代表ATM突变，包括一些没有毛细血管扩张症。我们的发现扩展了与ATM突变相关的表型范围。
Ataxia-telangiectasia (A-T) is an autosomal recessive disorder characterized by cerebellar degeneration, immunodeficiency, chromosomal instability, radiosensitivity, and cancer predisposition. A-T cells are sensitive to ionizing radiation and radiomimetic chemicals and fail to activate cell-cycle checkpoints after treatment with these agents. The responsible gene, ATM, encodes a large protein kinase with a phosphatidylinositol 3-kinase-like domain. The typical A-T phenotype is caused, in most cases, by null ATM alleles that truncate or severely destabilize the ATM protein. Rare patients with milder manifestations of the clinical or cellular characteristics of the disease have been reported and have been designated "A-T variants." A special variant form of AT is A-T-Fresno which combines a typical A-T phenotype with microcephaly and mental retardation. The possible association of these syndromes with ATM is both important for understanding their molecular basis and essential for counseling and diagnostic purposes. We quantified ATM-protein levels in six A-T variants, and we searched their ATM genes for mutations. Cell lines from these patients exhibited considerable variability in radiosensitivity while showing the typical radioresistant DNA synthesis of A-T cells. Unlike classical A-T patients, these patients exhibited 1%-17% of the normal level of ATM. The underlying ATM genotypes were either homozygous for mutations expected to produce mild phenotypes or compound heterozygotes for a mild and a severe mutation. An A-(Fresno) cell line was found devoid of the ATM protein and homozygous for a severe ATM mutation. We conclude that certain "A-T variant" phenotypes represent ATM mutations, including some of those without telangiectasia. Our findings extend the range of phenotypes associated with ATM mutations.