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. 2025 Jan 24;45(1):67.
doi: 10.1007/s10875-025-01857-3.

ATM Expression and Activation in Ataxia Telangiectasia Patients with and without Class Switch Recombination Defects

Fereshte Salami #  1   2 , Tannaz Moeini Shad #  1   2 , Nazanin Fathi  1   2 , Hanieh Mojtahedi  1   2 , Marzie Esmaeili  1   2 , Sepideh Shahkarami  1   3   4 , Ladan Gol Mohammad Pour Afrakoti  5 , Parisa Amirifar  1   2 , Samaneh Delavari  1   2 , Hassan Nosrati  6 , Azadehsadat Razavi  1 , Mohammad Reza Ranjouri  1   2 , Mahsa Yousefpour  1   2 , Zahra Hamidi Esfahani  1   2 , Gholamreza Azizi  7   8 , Mahmoudreza Ashrafi  9 , Nima Rezaei  1   2 , Reza Yazdani  10   11 , Hassan Abolhassani  12   13
Affiliations

ATM Expression and Activation in Ataxia Telangiectasia Patients with and without Class Switch Recombination Defects

Fereshte Salami et al. J Clin Immunol. .

Abstract

Background: 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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: Class switch recombination (CSR); Immunodeficiency; Inborn errors of immunity, primary immunodeficiency, ataxia telangiectasia (A-T); Ionizing radiation; Phosphorylated ATM (p-ATM); Severe and mild.

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Conflict of interest statement

Declarations. Ethics Approval: This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Tehran University of Medical Sciences (IR.TUMS.CHMC.REC.1398.030). Consent to Participate: Informed consent was obtained from all individuals participating in the study. Consent for Publication: The authors affirm that human research participants provided informed consent for publication of the data in this manuscript. Conflict of Interest: The authors declare that they do not have a conflict of interest.

Figures

Fig. 1
Fig. 1
Western blot analysis of the expression and p-Ser1981- autophosphorylation of ATM protein in patient P9 (homozygous frameshift mutation of p.Glu2087LysfsTer9), P6 (homozygous splice site mutation of c.6453–2 A > G) and healthy controls (HC2 and HC3). Whole-cell extracts were collected from patients and normal ATM-positive controls and then harvested at one minute post-irradiation (0.5 Gy). Two lanes per lysate are shown, one unirradiated (-) and one irradiated (+) (activated ATM). Detectable expression and activity of ATM protein was present in P6 in comparison with HC3. P, patient; C, control; IR, irradiation
Fig. 2
Fig. 2
The level of phosphorylated and non-phosphorylated (p-Ser1981) ATM protein expression by western blot method in A-T patients and control group (Mean ± SD, Table S1). For more detailed presentred of data in median and interquinltie range please see Table S2. CSR: Class switching recombination. *P-value < 0.05 is statistically significant between mild and severe patients
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