Primary microcephaly, impaired DNA replication, and genomic instability caused by compound heterozygous ATR mutations

Hum Mutat. 2013 Feb;34(2):374-84. doi: 10.1002/humu.22245. Epub 2012 Dec 20.


Ataxia telangiectasia-mutated (ATM) and ataxia telangiectasia and Rad3-related (ATR) kinases are two key regulators of DNA-damage responses (DDR) that are mainly activated in response to DNA double-strand breaks and single-stranded DNA damages, respectively. Seckel syndrome, a rare genetic disorder characterized by a microcephaly and a markedly reduced body size, has been associated with defective ATR-dependent DNA damage signaling. However, the only human genetic ATR defect reported so far is a hypomorphic splicing mutation identified in five related individuals with Seckel syndrome. Here, we report the first case of primary microcephaly with compound heterozygous mutations in ATR: a 540 kb genomic deletion on one allele and a missense mutation leading to splice dysregulation on the other, which ultimately lead to a sharp decrease in ATR expression. DNA combing technology revealed a profound spontaneous alteration of several DNA replication parameters in patient's cells and FISH analyses highlighted the genomic instability caused by ATR deficiency. Collectively, our results emphasize the crucial role for ATR in the control of DNA replication, and reinforce the complementary and nonredundant contributions of ATM and ATR in human cells to face DNA damages and warrant genome integrity.

Publication types

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

MeSH terms

  • Alleles
  • Animals
  • Ataxia Telangiectasia Mutated Proteins
  • Base Sequence
  • Blotting, Western
  • Cell Cycle Proteins / genetics*
  • Cell Line
  • Child
  • Comparative Genomic Hybridization
  • DNA Breaks, Double-Stranded
  • DNA Replication*
  • DNA, Single-Stranded*
  • DNA-Binding Proteins / genetics*
  • Female
  • Fibroblasts / cytology
  • Fibroblasts / metabolism
  • Fluorescent Antibody Technique
  • Gene Deletion
  • Genome-Wide Association Study
  • Genomic Instability*
  • Heterozygote
  • Humans
  • In Situ Hybridization, Fluorescence
  • Male
  • Mice
  • Microcephaly / genetics*
  • Molecular Sequence Data
  • Mutation, Missense
  • Protein-Serine-Threonine Kinases / genetics*
  • RNA Splicing
  • Signal Transduction
  • Tumor Suppressor Proteins / genetics*


  • Cell Cycle Proteins
  • DNA, Single-Stranded
  • DNA-Binding Proteins
  • Tumor Suppressor Proteins
  • ATM protein, human
  • ATR protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Atm protein, mouse
  • Protein-Serine-Threonine Kinases