Impaired lymphocyte development and antibody class switching and increased malignancy in a murine model of DNA ligase IV syndrome
Copyright policy )Impaired lymphocyte development and antibody class switching and increased malignancy in a murine model of DNA ligase IV syndrome
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.
- Australian National University Australia
- University of Sussex United Kingdom
- University of Oxford United Kingdom
lymphocytes, 570, mice, 572, DNA Ligases, Cell Survival, knockout, cell survival, Mice, Animals, animal, immunoglobulin isotypes, Lymphocytes, thymus neoplasms, Mice, Knockout, disease models, Cell Differentiation, Syndrome, Thymus Neoplasms, antibody formation, syndrome, dna ligases, Immunoglobulin Class Switching, animals, Immunoglobulin Isotypes, Mice, Inbred C57BL, cell differentiation, Disease Models, Animal, QH0426, Antibody Formation, Mutation, inbred c57bl, mutation, immunoglobulin class switching
lymphocytes, 570, mice, 572, DNA Ligases, Cell Survival, knockout, cell survival, Mice, Animals, animal, immunoglobulin isotypes, Lymphocytes, thymus neoplasms, Mice, Knockout, disease models, Cell Differentiation, Syndrome, Thymus Neoplasms, antibody formation, syndrome, dna ligases, Immunoglobulin Class Switching, animals, Immunoglobulin Isotypes, Mice, Inbred C57BL, cell differentiation, Disease Models, Animal, QH0426, Antibody Formation, Mutation, inbred c57bl, mutation, immunoglobulin class switching
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