Menotta Michele, Biagiotti Sara, Spapperi Chiara, Orazi Sara, Rossi Luigia, Chessa Luciana, Leuzzi Vincenzo, D'Agnano Daniela, Soresina Annarosa, Micheli Roberto, Magnani Mauro
Department of Biomolecular Sciences, University of Urbino "Carlo Bo", 61029, Urbino, PU, Italy.
Department of Clinical and Molecular Medicine, University "La Sapienza", 00198, Rome, Italy.
Orphanet J Rare Dis. 2017 Jul 5;12(1):126. doi: 10.1186/s13023-017-0669-2.
Ataxia Telangiectasia (AT) is a rare incurable genetic disease, caused by biallelic mutations in the Ataxia Telangiectasia-Mutated (ATM) gene. Treatment with glucocorticoid analogues has been shown to improve the neurological symptoms that characterize this syndrome. Nevertheless, the molecular mechanism underlying the glucocorticoid action in AT patients is not yet understood. Recently, we have demonstrated that Dexamethasone treatment may partly restore ATM activity in AT lymphoblastoid cells by a new ATM transcript, namely ATMdexa1.
In the present study, the new ATMdexa1 transcript was also identified in vivo, specifically in the PMBCs of AT patients treated with intra-erythrocyte Dexamethasone (EryDex). In these patients it was also possible to isolate new "ATMdexa1 variants" originating from canonical and non-canonical splicing, each containing the coding sequence for the ATM kinase domain. The expression of the ATMdexa1 transcript family was directly related to treatment and higher expression levels of the transcript in patients' blood correlated with a positive response to Dexamethasone therapy. Neither untreated AT patients nor untreated healthy volunteers possessed detectable levels of the transcripts. ATMdexa1 transcript expression was found to be elevated 8 days after the drug infusion, while it decreased 21 days after treatment.
For the first time, the expression of ATM splicing variants, similar to those previously observed in vitro, has been found in the PBMCs of patients treated with EryDex. These findings show a correlation between the expression of ATMdexa1 transcripts and the clinical response to low dose dexamethasone administration.
共济失调毛细血管扩张症（AT）是一种罕见的不治之症遗传性疾病，由共济失调毛细血管扩张症突变（ATM）基因的双等位基因突变引起。已证明使用糖皮质激素类似物治疗可改善该综合征所特有的神经症状。然而，糖皮质激素在AT患者中作用的分子机制尚不清楚。最近，我们已经证明地塞米松治疗可能通过一种新的ATM转录本，即ATMdexa1，部分恢复AT淋巴母细胞中的ATM活性。
在本研究中，还在体内鉴定出了新的ATMdexa1转录本，具体是在接受红细胞内注射地塞米松（EryDex）治疗的AT患者的外周血单核细胞（PBMC）中。在这些患者中，还能够分离出来自经典和非经典剪接的新“ATMdexa1变体”，每个变体都包含ATM激酶结构域的编码序列。ATMdexa1转录本家族的表达与治疗直接相关，患者血液中该转录本的较高表达水平与对地塞米松治疗的阳性反应相关。未经治疗的AT患者和未经治疗的健康志愿者均未检测到转录本水平。发现药物输注后8天ATMdexa1转录本表达升高，而治疗后21天其表达下降。
首次在接受EryDex治疗的患者的PBMC中发现了与先前在体外观察到的类似的ATM剪接变体的表达。这些发现表明ATMdexa1转录本的表达与低剂量地塞米松给药的临床反应之间存在相关性。
