Scholarlink

Background <p>Ataxia telangiectasia (AT) is an autosomal recessive neurodegenerative disease. While heterozygous relatives of AT patients are known to be clinically healthy, a predisposition to various pathologies has been reported. Our aim was firstly, to further characterize the clinical features and broaden the spectrum of genetic pathogenic variants in AT patients. Secondly, we aimed to study the immune profiles of AT patients and their relatives to identify similarities or common biomarkers.</p> Methods <p>A Target Gene Sequencing for six patients suspected with AT was performed. Computational analysis was conducted to assess the pathogenicity of novel variants. The distribution of immune cells was assessed by flow cytometry in patients with AT, AT-like disorder, Friedreich ataxia, and in AT relatives. The expression pattern of candidate genes was evaluated by RT-qPCR.</p> Results <p>We identified and predicted the pathogenicity of novel variants in the <i>ATM</i> gene. Computational analysis suggested that the novel identified missense mutation could affect ATP binding pattern and ATM protein flexibility, while Alu element insertion could probably induces a premature stop codon. Furthermore, our results confirm the pathogenic effect of identified splicing mutations on the ATM transcript. Moreover, we noticed a high percentage of LTCD4 + and LTCD8 + senescent subsets in AT patients and a relative increase of the of intermediate and non-classical monocytes accompanied with a decrease of classical monocytes specifically in AT patients with truncated biallelic mutations which was intriguingly similar to the immune profile of AT parents. In addition, a difference of immune pattern was observed between AT patients with biallelic truncated mutations compared to those with at least one non-truncated mutation, with a variability intragroup. Gene expression analysis identified <i>FOXO3</i>, <i>IL33</i> and <i>METTL3</i> as putative genes that may yield clues into AT pathogenesis.</p> Conclusion <p>Taken together, our study expands the mutational spectrum of AT disease worldwide and further characterize the immune profile of AT patients uncovering a possible difference in some immune cellular subsets related to <i>ATM</i> mutation type and delineate putative immune abnormalities related to <i>ATM</i> heterozygosity among AT parents. Furthermore, dysregulation in <i>FOXO3</i>, <i>IL33</i> and <i>METTL3</i> expression could be related to disease severity.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Novel genetic variants identification and immune profiling in ataxia telangiectasia patients

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年2月19日

查看全文
  • Rim Jenni,
  • Hedia Klaa,
  • Asma Chikhaoui,
  • Khouloud Zayoud,
  • Emmanuelle Cochet,
  • Ichraf Kraoua,
  • Lydie Burglen,
  • Houda Yacoub-Youssef

摘要

Background

Ataxia telangiectasia (AT) is an autosomal recessive neurodegenerative disease. While heterozygous relatives of AT patients are known to be clinically healthy, a predisposition to various pathologies has been reported. Our aim was firstly, to further characterize the clinical features and broaden the spectrum of genetic pathogenic variants in AT patients. Secondly, we aimed to study the immune profiles of AT patients and their relatives to identify similarities or common biomarkers.

Methods

A Target Gene Sequencing for six patients suspected with AT was performed. Computational analysis was conducted to assess the pathogenicity of novel variants. The distribution of immune cells was assessed by flow cytometry in patients with AT, AT-like disorder, Friedreich ataxia, and in AT relatives. The expression pattern of candidate genes was evaluated by RT-qPCR.

Results

We identified and predicted the pathogenicity of novel variants in the ATM gene. Computational analysis suggested that the novel identified missense mutation could affect ATP binding pattern and ATM protein flexibility, while Alu element insertion could probably induces a premature stop codon. Furthermore, our results confirm the pathogenic effect of identified splicing mutations on the ATM transcript. Moreover, we noticed a high percentage of LTCD4 + and LTCD8 + senescent subsets in AT patients and a relative increase of the of intermediate and non-classical monocytes accompanied with a decrease of classical monocytes specifically in AT patients with truncated biallelic mutations which was intriguingly similar to the immune profile of AT parents. In addition, a difference of immune pattern was observed between AT patients with biallelic truncated mutations compared to those with at least one non-truncated mutation, with a variability intragroup. Gene expression analysis identified FOXO3, IL33 and METTL3 as putative genes that may yield clues into AT pathogenesis.

Conclusion

Taken together, our study expands the mutational spectrum of AT disease worldwide and further characterize the immune profile of AT patients uncovering a possible difference in some immune cellular subsets related to ATM mutation type and delineate putative immune abnormalities related to ATM heterozygosity among AT parents. Furthermore, dysregulation in FOXO3, IL33 and METTL3 expression could be related to disease severity.