Abstract
BackgroundAtaxia 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.ResultsIn 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.ConclusionsFor 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.
Highlights
Ataxia Telangiectasia (AT) is a rare incurable genetic disease, caused by biallelic mutations in the Ataxia Telangiectasia-Mutated (ATM) gene
These results suggest that the induction of the ATMdexa1
Aldo Isidori ref. #636/11), and all patients provided informed consent. This investigation has shown that the ATMdexa1 transcript is detectable in the whole blood of AT patients treated with EryDex
Summary
Ataxia Telangiectasia (AT) is a rare incurable genetic disease, caused by biallelic mutations in the Ataxia Telangiectasia-Mutated (ATM) gene. In the last few years, experimental investigations and clinical trials have provided evidence that short-term treatment with glucocorticoid (GC) analogues is able to improve neurological symptoms in AT patients [1,2,3,4] raising the possibility that cerebellar abnormalities may still be modified during the initial phase of cell loss [5]. This neurological improvement is transitory and disappears when oral GC administration is discontinued, and the benefit-to-risk balance limits the long-term administration of oral steroids. In treated patients it was possible to discover several additional ATMdexa variants
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