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DNA Ligase IV mutations identified in patients exhibiting development delay and immunodeficiency
journal contributionposted on 2023-06-07, 19:51 authored by Mark O'DriscollMark 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 Jeggo, Patrick Concannon
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.
Department affiliated with
- Sussex Centre for Genome Damage Stability Publications
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