title: Impaired lymphocyte development and antibody class switching and increased malignancy in a murine model of DNA ligase IV syndrome.
abstract: 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.
authors.affiliation: Henry Wellcome Building of Molecular Physiology, Oxford University, Oxford, United Kingdom.
authors.forename: Anastasia
authors.initials: A
authors.lastname: Nijnik
authors.forename: Sara
authors.initials: S
authors.lastname: Dawson
authors.forename: Tanya L
authors.initials: TL
authors.lastname: Crockford
authors.forename: Lisa
authors.initials: L
authors.lastname: Woodbine
authors.forename: Supawan
authors.initials: S
authors.lastname: Visetnoi
authors.forename: Sophia
authors.initials: S
authors.lastname: Bennett
authors.forename: Margaret
authors.initials: M
authors.lastname: Jones
authors.forename: Gareth D
authors.initials: GD
authors.lastname: Turner
authors.forename: Penelope A
authors.initials: PA
authors.lastname: Jeggo
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Goodnow
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Cornall
mesh_terms: D000818:Animals; D000917:Antibody Formation / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology*; D002470:Cell Survival; D011088:DNA Ligases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D004195:Disease Models, Animal; D017578:Immunoglobulin Class Switching / Q000276:immunology*; D007132:Immunoglobulin Isotypes / Q000276:immunology*; D008214:Lymphocytes / Q000166:cytology / Q000201:enzymology* / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D013577:Syndrome; D013953:Thymus Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000276:immunology / Q000473:pathology
chemical_list: D007132:Immunoglobulin Isotypes; D011088:DNA Ligases