DNA ligase IV mutations identified in patients exhibiting developmental delay and immunodeficiency

Mark O'Driscoll, Karen M. Cerosaletti, Pierre M. Girard, Yan Dai, Markus Stumm, Boris Kysela, Betsy Hirsch, Andrew Gennery, Susan E. Palmer, Jörg Seidel, Richard A. Gatti, Raymonda Varon, Marjorie A. Oettinger, Heidemarie Neitzel, Penny A. Jeggo, Patrick Concannon

Research output: Contribution to journalArticlepeer-review

391 Scopus citations


DNA ligase IV functions in DNA nonhomologous end-joining and V(D)J recombination. Four patients with features including immunodeficiency and developmental and growth delay were found to have mutations in the gene encoding DNA ligase IV (LIG4). Their clinical phenotype closely resembles the DNA damage response disorder, Nijmegen breakage syndrome (NBS). Some of the mutations identified in the patients directly disrupt the ligase domain while others impair the interaction between DNA ligase IV and Xrcc-4. Cell lines from the patients show pronounced radiosensitivity. Unlike NBS cell lines, they show normal cell cycle checkpoint responses but impaired DNA double-strand break rejoining. An unexpected V(D)J recombination phenotype is observed involving a small decrease in rejoining frequency coupled with elevated imprecision at signal junctions.

Original languageEnglish (US)
Pages (from-to)1175-1185
Number of pages11
JournalMolecular Cell
Issue number6
StatePublished - 2001

Bibliographical note

Funding Information:
We thank Dr. M. Lieber for providing the N114-P2 cells and Prof. K. Sperling for collaborating. Work contributing to this study in the P.A.J. laboratory was supported by the Human Frontiers Science Program, the Industry-funded UKCCCR Radiation Research Program, the Leukaemia Research Fund and European Union grant Figh CT 1999. Work contributing to this study in the P.C. laboratory was supported by a grant from the National Cancer Institute (CA57569).

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