RIDDLE immunodeficiency syndrome is linked to defects in 53BP1-mediated DNA damage signaling

Grant Stewart, Tatjana Stankovic, Philip Byrd, T Wechsler, Edward Miller, Aarnoud Huissoon, Mark Drayson, SC West, SJ Elledge, Alexander Taylor

Research output: Contribution to journalArticle

126 Citations (Scopus)


Cellular DNA double-strand break-repair pathways have evolved to protect the integrity of the genome from a continual barrage of potentially detrimental insults. Inherited mutations in genes that control this process result in an inability to properly repair DNA damage, ultimately leading to developmental defects and also cancer predisposition. Here, we describe a patient with a previously undescribed syndrome, which we have termed RIDDLE syndrome (radiosensitivity, immunodeficiency, dysmorphic features and learning difficulties), whose cells lack an ability to recruit 53BP1 to sites of DNA double-strand breaks. As a consequence, cells derived from this patient exhibit a hypersensitivity to ionizing radiation, cell cycle checkpoint abnormalities, and impaired end-joining in the recombined switch regions. Sequencing of TP53BP1 and other genes known to regulate ionizing radiation-induced 53BP1 foci formation in this patient failed to detect any mutations. Therefore, these data indicate the existence of a DNA double-strand break-repair protein that functions upstream of 53BP1 and contributes to the normal development of the human immune system.
Original languageEnglish
Pages (from-to)16910-5
Number of pages6
JournalNational Academy of Sciences. Proceedings
Issue number43
Publication statusPublished - 23 Oct 2007


  • radiosensitivity
  • DNA repair
  • cell cycle checkpoint
  • BRCA1


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