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

doi:10.1073/pnas.0708408104

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

*Cancer Research UK, Institute for Cancer Studies, Birmingham University, Vincent Drive, Edgbaston, Birmingham B15 2TT, United Kingdom;
^‡Cancer Research UK, Clare Hall Laboratories, London Research Institute, South Mimms, Hertfordshire EN6 3LD, United Kingdom;
^§Department of Immunology, Birmingham Heartlands Hospital, Birmingham, B9 5SS, United Kingdom;
^¶Division of Immunity and Infection, Birmingham University Medical School, Vincent Drive, Edgbaston, Birmingham B15 2TT, United Kingdom; and
^‖Howard Hughes Medical Institute, Department of Genetics, Harvard Partners Center for Genetics and Genomics, Harvard Medical School, 77 Avenue Louis Pasteur, Boston, MA 02115

Contributed by Stephen J. Elledge, September 6, 2007 (received for review July 6, 2007)

Abstract

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.

Footnotes

^†To whom correspondence may be addressed. E-mail: g.s.stewart{at}bham.ac.uk or selledge{at}genetics.med.harvard.edu
Author contributions: G.S.S. designed research; G.S.S., T.S., P.J.B., T.W., E.S.M., S.C.W., and S.J.E. performed research; A.H. and M.T.D. contributed new reagents/analytic tools; G.S.S., A.H., M.T.D., S.C.W., and S.J.E. analyzed data; and G.S.S. and A.M.R.T. wrote the paper.
The authors declare no conflict of interest.
This article contains supporting information online at www.pnas.org/cgi/content/full/0708408104/DC1.
Abbreviations:

DSBs,

DNA double strand breaks;

DSBR,

DSB repair;

CSR,

class switch recombination;

IR,

ionizing radiation;

IRIF,

IR-induced foci;

MEF,

mouse embryo fibroblast.
Freely available online through the PNAS open access option.