Analysis of novel missense ATR mutations reveals new splicing defects underlying Seckel syndrome

Marta Llorens-Agost, Janna Luessing, Amandine van Beneden, John Eykelenboom, Dawn O'Reilly, Louise S Bicknell, John J Reynolds, Marianne van Koegelenberg, Matthew E Hurles, Angela F Brady, Andrew P Jackson, Grant S Stewart, Noel F Lowndes

Research output: Contribution to journalArticlepeer-review


Ataxia Telangiectasia and Rad3 related (ATR) is one of the main regulators of the DNA damage response. It coordinates cell cycle checkpoint activation, replication fork stability, restart and origin firing to maintain genome integrity. Mutations of the ATR gene have been reported in Seckel patients, who suffer from a rare genetic disease characterized by severe microcephaly and growth retardation. Here, we report the case of a Seckel patient with compound heterozygous mutations in ATR. One allele has an intronic mutation affecting splicing of neighboring exons, the other an exonic missense mutation, producing the variant p.Lys1665Asn, of unknown pathogenicity. We have modeled this novel missense mutation, as well as a previously described missense mutation p.Met1159Ile, and assessed their effect on ATR function. Interestingly, our data indicate that both missense mutations have no direct effect on protein function, but rather result in defective ATR splicing. These results emphasize the importance of splicing mutations in Seckel Syndrome.

Original languageEnglish
Pages (from-to)1847-1853
Number of pages7
JournalHuman mutation
Issue number12
Early online date10 Sept 2018
Publication statusPublished - Dec 2018

Bibliographical note

© 2018 Wiley Periodicals, Inc.


  • Animals
  • Ataxia Telangiectasia Mutated Proteins/genetics
  • Cell Line
  • Chickens
  • Dwarfism/genetics
  • Exons
  • Humans
  • Introns
  • Microcephaly/genetics
  • Mutation, Missense
  • RNA Splicing
  • Exome Sequencing
  • Splicing Regulation
  • Seckel Syndrome


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