1. Dexamethasone Partially Rescues Ataxia Telangiectasia-mutated (ATM) Deficiency in Ataxia Telangiectasia by Promoting a Shortened Protein Variant Retaining Kinase Activity
- Author
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Marzia Bianchi, Mauro Magnani, Luciana Chessa, Sara Biagiotti, and Michele Menotta
- Subjects
congenital, hereditary, and neonatal diseases and abnormalities ,Ataxia ,Genotype ,Cell Cycle Proteins ,Ataxia Telangiectasia Mutated Proteins ,Protein Serine-Threonine Kinases ,Biology ,Biochemistry ,Dexamethasone ,Cell Line ,Fungal Proteins ,Ataxia Telangiectasia ,Open Reading Frames ,medicine ,Humans ,Lymphocytes ,Cycloheximide ,Kinase activity ,Codon ,Glucocorticoids ,Molecular Biology ,Alleles ,Protein Synthesis Inhibitors ,Models, Genetic ,Tumor Suppressor Proteins ,Phosphotransferases ,Single-Strand Specific DNA and RNA Endonucleases ,Alternative splicing ,nutritional and metabolic diseases ,Genetic Variation ,Cell Biology ,medicine.disease ,Molecular biology ,Protein Structure, Tertiary ,DNA-Binding Proteins ,Alternative Splicing ,Protein kinase domain ,Mutation ,RNA splicing ,Ataxia-telangiectasia ,CHD4 ,medicine.symptom ,Ataxia telangiectasia and Rad3 related ,HeLa Cells - Abstract
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.
- Published
- 2012