Journal of Biological Chemistry
Volume 287, Issue 49, 30 November 2012, Pages 41352-41363
Journal home page for Journal of Biological Chemistry

Cell Biology
Dexamethasone Partially Rescues Ataxia Telangiectasia-mutated (ATM) Deficiency in Ataxia Telangiectasia by Promoting a Shortened Protein Variant Retaining Kinase Activity*

https://doi.org/10.1074/jbc.M112.344473Get rights and content
Under a Creative Commons license
open access

Ataxia telangiectasia (AT) is a rare genetic disease, still incurable, resulting from biallelic mutations in the ataxia telangiectasia-mutated (ATM) gene. Recently, short term treatment with glucocorticoid analogues improved neurological symptoms characteristic of this syndrome. Nevertheless, the molecular mechanism involved in glucocorticoid action in AT patients is not yet known. Here we describe, for the first time in mammalian cells, a short direct repeat-mediated noncanonical splicing event induced by dexamethasone, which leads to the skipping of mutations upstream of nucleotide residue 8450 of ATM coding sequence. The resulting transcript provides an alternative ORF translated in a new ATM variant with the complete kinase domain. This miniATM variant was also highlighted in lymphoblastoid cell lines from AT patients and was shown to be likely active. In conclusion, dexamethasone treatment may partly restore ATM activity in ataxia telangiectasia cells by a new molecular mechanism that overcomes most of the mutations so far described within this gene.

Alternative Splicing
Ataxia
Genetic Diseases
Glucocorticoids
Translation
SDR-mediated Splicing

Cited by (0)

*

This work was supported in part by grants from FanoAteneo and Associazione Nazionale AT “Davide De Marini.”

1

Both authors contributed equally to this work.