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Impaired lymphocyte development and antibody class switching and increased malignancy in a murine model of DNA ligase IV syndrome

journal contribution
posted on 2023-06-07, 15:12 authored by Anastasia Nijnik, Sara Dawson, Lisa Woodbine, Supawan Visetnoi, Sophia Bennett, Margaret Jones, Gareth D Turner, Penny Jeggo, Christopher C Goodnow, Richard J Cornall
Hypomorphic mutations in DNA ligase IV (LIG4) cause a human syndrome of immunodeficiency, radiosensitivity, and growth retardation due to defective DNA repair by the nonhomologous end-joining (NHEJ) pathway. Lig4-null mice are embryonic lethal, and better mouse models are needed to study human LigIV syndrome. We recently identified a viable mouse strain with a Y288C hypomorphic mutation in the Lig4 gene. Lig4Y288C mice exhibit a greater than 10-fold reduction of LigIV activity in vivo and recapitulate the immunodeficiency and growth retardation seen in human patients. Here, we have demonstrated that the Lig4Y288C mutation leads to multiple defects in lymphocyte development and function, including impaired V(D)J recombination, peripheral lymphocyte survival and proliferation, and B cell class switch recombination. We also highlight a high incidence of thymic tumors in the Lig4Y288C mice, suggesting that wild-type LigIV protects against malignant transformation. These findings provide explanations for the complex lymphoid phenotype of human LigIV syndrome.

History

Publication status

  • Published

Journal

Journal of Clinical Investigation

ISSN

00219738

Publisher

American Society for Clinical Investigation

Issue

6

Volume

119

Page range

1696-1705

Department affiliated with

  • Sussex Centre for Genome Damage Stability Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2009-12-21

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