Ataxia-telangiectasia (AT) is a rare inherited recessive disorder which is caused by a mutated Ataxia-telangiectasia mutated (ATM) gene. Hallmarks include chromosomal instability, cancer predisposition and increased sensitivity to ionizing radiation. The ATM protein plays an important role in signaling of DNA double-strand breaks (DSB), thereby phosphorylating the histone H2A.X. Non-functional ATM protein leads to defects in DNA damage response, unresolved DSBs and genomic instability. The aim of this study was to evaluate chromosomal aberrations and γH2A.X foci as potential radiation sensitivity biomarkers in AT patients. For this purpose, lymphocytes of 8 AT patients and 10 healthy controls were irradiated and induced DNA damage and DNA repair capacity were detected by the accumulation of γH2A.X foci. The results were heterogeneous among AT patients. Evaluation revealed 2 AT patients with similar γH2A.X foci numbers as controls after 1 h while 3 patients showed a lower induction. In regard to DNA repair, 3 of 5 AT patients showed poor damage repair. Therefore, DNA damage induction and DNA repair as detected by H2A.X phosphorylation revealed individual differences, seems to depend on the underlying individual mutation and thus appears not well suited as a biomarker for radiation sensitivity. In addition, chromosomal aberrations were analyzed by mFISH. An increased frequency of spontaneous chromosomal breakage was characteristic for AT cells. After irradiation, significantly increased rates for non-exchange aberrations, translocations, complex aberrations and dicentric chromosomes were observed in AT patients compared to controls. The results of this study suggested, that complex aberrations and dicentric chromosomes might be a reliable biomarker for radiation sensitivity in AT patients, while non-exchange aberrations and translocations identified both, spontaneous and radiation-induced chromosomal instability.

共济失调毛细血管扩张症（AT）是一种罕见的遗传性隐性疾病，由突变型共济失调毛细血管扩张症（ATM) 基因。标志包括染色体不稳定、癌症易感性和对电离辐射的敏感性增加。ATM 蛋白在 DNA 双链断裂 (DSB) 的信号传导中起重要作用，从而使组蛋白 H2A.X 磷酸化。非功能性 ATM 蛋白导致 DNA 损伤反应缺陷、未解决的 DSB 和基因组不稳定性。本研究的目的是评估作为 AT 患者潜在辐射敏感性生物标志物的染色体畸变和 γH2A.X 病灶。为此，对 8 名 AT 患者和 10 名健康对照的淋巴细胞进行了照射，并通过 γH2A.X 病灶的积累检测了诱导的 DNA 损伤和 DNA 修复能力。结果在 AT 患者中存在异质性。评估显示 2 名 AT 患者具有相似的 γH2A。1 小时后 X 焦点数作为对照，而 3 名患者显示出较低的诱导。在 DNA 修复方面，5 名 AT 患者中有 3 名表现出较差的损伤修复。因此，通过 H2A.X 磷酸化检测到的 DNA 损伤诱导和 DNA 修复揭示了个体差异，似乎取决于潜在的个体突变，因此似乎不太适合作为辐射敏感性的生物标志物。此外，通过 mFISH 分析染色体畸变。自发染色体断裂频率增加是 AT 细胞的特征。照射后，与对照组相比，在 AT 患者中观察到非交换畸变、易位、复杂畸变和双着丝粒染色体的发生率显着增加。这项研究的结果表明，