Underexpression and abnormal localization of ATM products in ataxia telangiectasia patients bearing ATM missense mutations

Eur J Hum Genet. 2012 Mar;20(3):305-12. doi: 10.1038/ejhg.2011.196. Epub 2011 Nov 9.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Ataxia Telangiectasia / genetics*
  • Ataxia Telangiectasia / metabolism*
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins / genetics*
  • Cell Cycle Proteins / metabolism*
  • Cell Line
  • Child
  • Child, Preschool
  • DNA-Binding Proteins / genetics*
  • DNA-Binding Proteins / metabolism*
  • Female
  • Gene Expression
  • Histones / metabolism
  • Humans
  • Infant
  • Male
  • Mutation, Missense*
  • Phosphorylation
  • Polymorphism, Single Nucleotide
  • Protein Serine-Threonine Kinases / genetics*
  • Protein Serine-Threonine Kinases / metabolism*
  • Protein Transport
  • Transcription, Genetic
  • Tumor Suppressor Proteins / genetics*
  • Tumor Suppressor Proteins / metabolism*


  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • H2AX protein, human
  • Histones
  • Tumor Suppressor Proteins
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein Serine-Threonine Kinases