期刊
JOURNAL OF CLINICAL INVESTIGATION
卷 119, 期 6, 页码 1696-1705出版社
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI32743
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资金
- Wellcome Trust
- NIHR Biomedical Research Centre Programme
- Medical Research Council
- Association For International Cancer Research
- EU [LSHG-CT-2005-512113]
- United Kingdom Department of Health
- MRC [G0500897] Funding Source: UKRI
- Medical Research Council [G0300662B, G0500897] Funding Source: researchfish
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. Lig4(Y288C) 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 Lig4(Y288C) 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 Lig4(Y288C) mice, suggesting that wild-type LigIV protects against malignant transformation. These findings provide explanations for the complex lymphoid phenotype of human LigIV syndrome.
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