Ataxia telangiectasia: more variation at clinical and cellular levels

Clin Genet. 2015 Mar;87(3):199-208. doi: 10.1111/cge.12453. Epub 2014 Sep 8.


Ataxia telangiectasia (A-T) is a rare recessively inherited disorder resulting in a progressive neurological decline. It is caused by biallelic mutation of the ATM gene that encodes a 370 kDa serine/threonine protein kinase responsible for phosphorylating many target proteins. ATM is activated by auto(trans)phosphorylation in response to DNA double strand breaks and leads to the activation of cell cycle checkpoints and either DNA repair or apoptosis as part of the cellular response to DNA damage. The allelic heterogeneity in A-T is striking. While the majority of mutations are truncating, leading to instability and loss of the ATM protein from the allele, a significant proportion of patients carry one of a small number of mutations that are either missense or leaky splice site mutations resulting in retention of some ATM with activity. The allelic heterogeneity in ATM, therefore, results in an equally striking clinical heterogeneity. There is also locus heterogeneity because mutation of the MRE11 gene can cause an obvious A-T like disorder both clinically and also at the cellular level and mutation of the RNF168 gene results in a much milder clinical phenotype, neurologically, with the major clinical feature being an immunological defect.

Keywords: ATM; ataxia; kinase activity; telangiectasia.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Age of Onset
  • Ataxia Telangiectasia / complications
  • Ataxia Telangiectasia / diagnosis*
  • Ataxia Telangiectasia / epidemiology
  • Ataxia Telangiectasia / genetics
  • Ataxia Telangiectasia / metabolism
  • Ataxia Telangiectasia Mutated Proteins / deficiency
  • Ataxia Telangiectasia Mutated Proteins / genetics
  • DNA-Binding Proteins / genetics
  • Disease Progression
  • Enzyme Activation
  • Genetic Heterogeneity
  • Humans
  • MRE11 Homologue Protein
  • Mutation
  • Neoplasms / etiology
  • Phenotype
  • Signal Transduction
  • Ubiquitin-Protein Ligases / genetics


  • DNA-Binding Proteins
  • MRE11 protein, human
  • RNF168 protein, human
  • Ubiquitin-Protein Ligases
  • Ataxia Telangiectasia Mutated Proteins
  • MRE11 Homologue Protein