Salami Fereshte, Shad Tannaz Moeini, Fathi Nazanin, Mojtahedi Hanieh, Esmaeili Marzie, Shahkarami Sepideh, Afrakoti Ladan Gol Mohammad Pour, Amirifar Parisa, Delavari Samaneh, Nosrati Hassan, Razavi Azadehsadat, Ranjouri Mohammad Reza, Yousefpour Mahsa, Esfahani Zahra Hamidi, Azizi Gholamreza, Ashrafi Mahmoudreza, Rezaei Nima, Yazdani Reza, Abolhassani Hassan
Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children´s Medical Center, Tehran University of Medical Sciences, 62 Qarib St., Keshavarz Blvd, Tehran, 14194, Iran.
Primary Immunodeficiency Diseases Network (PIDNet), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
J Clin Immunol. 2025 Jan 24;45(1):67. doi: 10.1007/s10875-025-01857-3.
Ataxia telangiectasia mutated (ATM) kinase plays a critical role in DNA double-strand break (DSB) repair. Ataxia telangiectasia (A-T) patients exhibit abnormalities in immunoglobulin isotype expression and class switch recombination (CSR). This study investigates the role of residual ATM kinase expression and activity in the severity of A-T disease.
A-T patients with defined genetic diagnoses were classified based on CSR and based on the severity of their medical complications. Isolated peripheral blood mononuclear cells from any patient were evaluated before and after exposure to 0.5 Gy ionizing radiation for one minute. Western blotting was performed to identify the expression of ATM and phosphorylated ATM (p-ATM) proteins compared to age-sex-matched healthy controls.
In severe A-T patients (n = 6), the majority (66.7%) had frameshift mutations, while 33.3% had nonsense mutations in the ATM gene. The mild group (n = 3) had two cases of splice errors and one missense mutation. All patients with CSR defect had elevated IgM serum levels, whereas all switched immunoglobulins were reduced in them. Expression of ATM and p-ATM proteins was significantly lower (p = 0.01) in all patients compared to healthy controls, both pre-and post- and post-radiation. Additionally, low ATM and p-ATM protein expression levels were linked with the clinical severity of patients but were not correlated with CSR defects.
Expression and activation of ATM protein were defective in A-T patients compared to healthy controls. Altered expression of ATM and p-ATM proteins may have potential clinical implications for prognostic evaluation and symptom severity assessment in individuals with A-T.
共济失调毛细血管扩张症突变（ATM）激酶在DNA双链断裂（DSB）修复中起关键作用。共济失调毛细血管扩张症（A-T）患者在免疫球蛋白同种型表达和类别转换重组（CSR）方面表现异常。本研究调查了残余ATM激酶表达和活性在A-T疾病严重程度中的作用。
根据CSR以及医疗并发症的严重程度，对已明确基因诊断的A-T患者进行分类。在暴露于0.5 Gy电离辐射一分钟之前和之后，对任何患者分离的外周血单个核细胞进行评估。与年龄和性别匹配的健康对照相比，进行蛋白质免疫印迹以鉴定ATM和磷酸化ATM（p-ATM）蛋白的表达。
在重度A-T患者（n = 6）中，大多数（66.7%）有移码突变，而33.3%在ATM基因中有无义突变。轻度组（n = 3）有两例剪接错误和一例错义突变。所有CSR缺陷患者的血清IgM水平均升高，而所有转换的免疫球蛋白均降低。与健康对照相比，所有患者在辐射前后ATM和p-ATM蛋白的表达均显著降低（p = 0.01）。此外，低ATM和p-ATM蛋白表达水平与患者的临床严重程度相关，但与CSR缺陷无关。
与健康对照相比，A-T患者中ATM蛋白的表达和激活存在缺陷。ATM和p-ATM蛋白表达的改变可能对A-T患者的预后评估和症状严重程度评估具有潜在的临床意义。
