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

• Published in: The Journal of clinical investigation Vol. 119; no. 6; pp. 1696 - 1705
• Main Authors: Nijnik, Anastasia, Dawson, Sara, Crockford, Tanya L, Woodbine, Lisa, Visetnoi, Supawan, Bennett, Sophia, Jones, Margaret, Turner, Gareth D, Jeggo, Penelope A, Goodnow, Christopher C, Cornall, Richard J
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.06.2009
• Subjects: Abnormalities; Animals; Antibody Formation - immunology; Biomedical research; Bone marrow; Cell Differentiation - immunology; Cell Survival; Disease Models, Animal; DNA damage; DNA Ligases - deficiency; DNA Ligases - genetics; DNA Ligases - metabolism; Flow cytometry; Gene mutations; Genetic aspects; Health aspects; Immune system; Immunodeficiency; Immunoglobulin Class Switching - immunology; Immunoglobulin Isotypes - immunology; Kinases; Ligases; Lymphocytes; Lymphocytes - cytology; Lymphocytes - enzymology; Lymphocytes - immunology; Mice; Mice, Inbred C57BL; Mice, Knockout; Mutation; Mutation - genetics; Physiological aspects; Physiology; Risk factors; Syndrome; Thymus gland; Thymus Neoplasms - enzymology; Thymus Neoplasms - genetics; Thymus Neoplasms - immunology; Thymus Neoplasms - pathology; United Kingdom
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/jci32743

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.