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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.

Original publication

DOI

10.1172/JCI32743

Type

Journal article

Journal

J Clin Invest

Publication Date

06/2009

Volume

119

Pages

1696 - 1705

Keywords

Animals, Antibody Formation, Cell Differentiation, Cell Survival, DNA Ligases, Disease Models, Animal, Immunoglobulin Class Switching, Immunoglobulin Isotypes, Lymphocytes, Mice, Mice, Inbred C57BL, Mice, Knockout, Mutation, Syndrome, Thymus Neoplasms