| Impaired lymphocyte development and antibody class switching and increased malignancy in a murine model of DNA ligase IV syndrome. | |
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MedLine Citation:
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PMID: 19451691 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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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. |
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Authors:
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Anastasia Nijnik; Sara Dawson; Tanya L Crockford; Lisa Woodbine; Supawan Visetnoi; Sophia Bennett; Margaret Jones; Gareth D Turner; Penelope A Jeggo; Christopher C Goodnow; Richard J Cornall |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2009-05-18 |
Journal Detail:
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Title: The Journal of clinical investigation Volume: 119 ISSN: 1558-8238 ISO Abbreviation: J. Clin. Invest. Publication Date: 2009 Jun |
Date Detail:
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Created Date: 2009-06-02 Completed Date: 2009-07-24 Revised Date: 2009-11-18 |
Medline Journal Info:
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Nlm Unique ID: 7802877 Medline TA: J Clin Invest Country: United States |
Other Details:
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Languages: eng Pagination: 1696-705 Citation Subset: AIM; IM |
Affiliation:
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Henry Wellcome Building of Molecular Physiology, Oxford University, Oxford, United Kingdom. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Animals Antibody Formation / immunology Cell Differentiation / immunology* Cell Survival DNA Ligases / deficiency, genetics, metabolism* Disease Models, Animal Immunoglobulin Class Switching / immunology* Immunoglobulin Isotypes / immunology* Lymphocytes / cytology, enzymology*, immunology* Mice Mice, Inbred C57BL Mice, Knockout Mutation / genetics Syndrome Thymus Neoplasms / enzymology*, genetics, immunology, pathology |
| Grant Support | |
ID/Acronym/Agency:
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//Department of Health; //Medical Research Council; //Wellcome Trust |
| Chemical | |
Reg. No./Substance:
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0/Immunoglobulin Isotypes; EC 6.5.1.-/DNA Ligases |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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