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Underexpression and abnormal localization of ATM products in ataxia telangiectasia patients bearing ATM missense mutations
- Publication Year :
- 2011
- Publisher :
- Nature Publishing Group, 2011.
-
Abstract
- Ataxia telangiectasia (A-T) is a rare autosomal recessive disorder characterized by progressive cerebellar ataxia, oculocutaneous telangiectasia, immune defects and predisposition to malignancies. A-T is caused by biallelic inactivation of the ATM gene, in most cases by frameshift or nonsense mutations. More rarely, ATM missense mutations with unknown consequences on ATM function are found, making definitive diagnosis more challenging. In this study, a series of 15 missense mutations, including 11 not previously reported, were identified in 16 patients with clinical diagnosis of A-T belonging to 14 families and 1 patient with atypical clinical features. ATM function was evaluated in patient lymphoblastoid cell lines by measuring H2AX and KAP1 phosphorylation in response to ionizing radiation, confirming the A-T diagnosis for 16 cases. In accordance with previous studies, we showed that missense mutations associated with A-T often lead to ATM protein underexpression (15 out of 16 cases). In addition, we demonstrated that most missense mutations lead to an abnormal cytoplasmic localization of ATM, correlated with its decreased expression. This new finding highlights ATM mislocalization as a new mechanism of ATM dysfunction, which may lead to therapeutic strategies for missense mutation associated A-T.
- Subjects :
- Male
Transcription, Genetic
Nonsense mutation
Mutation, Missense
Gene Expression
Cell Cycle Proteins
Ataxia Telangiectasia Mutated Proteins
Biology
Protein Serine-Threonine Kinases
medicine.disease_cause
Polymorphism, Single Nucleotide
Article
Frameshift mutation
Cell Line
Histones
Ataxia Telangiectasia
Genetics
medicine
Missense mutation
Humans
Phosphorylation
Telangiectasia
Child
Genetics (clinical)
Mutation
Tumor Suppressor Proteins
Infant
medicine.disease
Molecular biology
DNA-Binding Proteins
Protein Transport
Histone
Child, Preschool
Ataxia-telangiectasia
biology.protein
Female
medicine.symptom
Subjects
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....c88b25b7e6e1b5971049560d2154d6ed