Three new cases of ataxia-telangiectasia-like disorder: No impairment of the ATM pathway, but S-phase checkpoint defect

Hum Mutat. 2019 Oct;40(10):1690-1699. doi: 10.1002/humu.23773. Epub 2019 May 15.


Ataxia-telangiectasia-like disorder (ATLD) is a rare genomic instability syndrome caused by biallelic variants of MRE11 (meiotic recombination 11) characterized by progressive cerebellar ataxia and typical karyotype abnormalities. These symptoms are common to those of ataxia-telangiectasia, which is consistent with the key role of MRE11 in ataxia-telangiectasia mutated (ATM) activation after DNA double-strand breaks. Three unrelated French patients were referred with ataxia. Only one had typical karyotype abnormalities. Unreported biallelic MRE11 variants were found in these three cases. Interestingly, one variant (c.424G>A) was present in two cases and haplotype analysis strongly suggested a French founder variant. Variants c.544G>A and c.314+4_314+7del lead to splice defects. The level of MRE11 in lymphoblastoid cell lines was consistently and dramatically reduced. Functional consequences were evaluated on activation of the ATM pathway via phosphorylation of ATM targets (KAP1 and CHK2), but no consistent defect was observed. However, an S-phase checkpoint activation defect after camptothecin was observed in these patients with ATLD. In conclusion, we report the first three French ATLD patients and a French founder variant, and propose an S-phase checkpoint activation study to evaluate the pathogenicity of MRE11 variants.

Keywords: MRN; ataxia; ataxia-telangiectasia mutated (ATM); ataxia-telangiectasia-like disorder (ATLD); checkpoint; meiotic recombination 11 (MRE11).

Publication types

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

MeSH terms

  • Ataxia Telangiectasia / diagnosis*
  • Ataxia Telangiectasia / etiology*
  • Ataxia Telangiectasia Mutated Proteins / genetics
  • Ataxia Telangiectasia Mutated Proteins / metabolism
  • Cell Line, Tumor
  • Child
  • Disease Susceptibility
  • Female
  • Gene Expression Profiling
  • Genetic Association Studies
  • Genetic Predisposition to Disease
  • Haplotypes
  • Humans
  • Infant
  • MRE11 Homologue Protein / genetics
  • MRE11 Homologue Protein / metabolism
  • Magnetic Resonance Imaging
  • Mutation
  • Phenotype
  • RNA Splicing
  • S Phase Cell Cycle Checkpoints / genetics
  • Signal Transduction
  • Transcriptome


  • MRE11 protein, human
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • MRE11 Homologue Protein

Supplementary concepts

  • Ataxia Telangiectasia Like Disorder