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Phenotypes Associated with This Genotype
Genotype
MGI:4437271
Allelic
Composition
Lig4tm2.1Fwa/Lig4tm2.1Fwa
Genetic
Background
involves: 129S6/SvEvTac
Find Mice Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Lig4tm2.1Fwa mutation (0 available); any Lig4 mutation (29 available)
phenotype observed in females
phenotype observed in males
N normal phenotype
nervous system
• medulloblastoma in 1 out of 44 mice

mortality/aging
• reduced life span

growth/size/body
• reduced body size at birth, 4 and 20 weeks of age
• reduced body weight at 4 and 20 weeks of age
• growth retardation at 4 months of age

cellular
• severely impaired recombination signal (RS) joining in mutant embryonic stem cells
• largely preserved coding joins formation, but imprecise RS joins in thymocytes
• extensive deletions within RS joins in thymocytes
• relatively normal joins could be recovered
• markedly reduced viability and increased apoptosis when simultaneously stained for annexin-V and 7-Aminoactinomycin D (7-AAD) for in vitro activated mutant splenic T cells
• increased radiation sensitivity in mutant mouse embryonic fibroblasts
• dramatic defect of splenic T cell proliferation, as assessed by 5,6-carboxyfluorescein succinimidyl ester (CFSE) dilution in vitro in the presence of anti-CD3 monoclonal antibody (mAb) in combination with either anti-CD28 mAb or IL-2
• 20% of the metaphases in mutant T cells contain aberrancies with the majority being chromosomal breaks and translocations, as compared to <2% chromosomal aberrancies in heterozygous cells

reproductive system
• fertility of mutant mice is severely compromised

immune system
• significantly reduced B220+ cells in the bone marrow
• majority of B220+ IgM- cells expressed CD43, indicating an incomplete block at the pro-B cell stage
• significantly reduced B220+ IgM+ B cells in the spleen
• a restricted repertoire of the splenic B cells
• clonal rearrangements or deletion of the Jbeta1 cluster in the vast majority of the tumors (8 of 13)
• clonal rearrangements involving the Jbeta2 cluster in several of the tumors
• a restricted T cell receptor (TCR) Vbeta repertoire in the spleen
• a largely polyclonal TCR Vbeta repertoire in the thymus
• drastically reduced absolute number of CD4_CD8_ double-negative (DN) T cell
• accumulation of DN thymocytes at the CD44_ CD25+ DN3 stage of development
• drastically reduced absolute number of CD4+ CD8+ double-positive T cell
• a lower number of transitional, follicular, and marginal zone splenic B cells
• drastically reduced absolute number of CD4+ T cell in the mutant thymus and spleen
• drastically reduced absolute number of CD8+ T cell in the mutant thymus and spleen
• CD4+ CD25hi Foxp3+ regulatory T cells in mesenteric lymph nodes
• mild architectural abnormalities with conserved demarcation between the cortex and the small-sized medulla
• overall preservation of the thymic architecture and of the corticomedullary demarcation
• decreased number in total thymic cellularity
• markedly reduced total cellularity in the spleen
• markedly reduced viability and increased apoptosis when simultaneously stained for annexin-V and 7-Aminoactinomycin D (7-AAD) for in vitro activated mutant splenic T cells
• modest inflammatory infiltrates (mainly composed of T lymphocytes and neutrophils) in the gut
• spontaneously produced higher titers of 2,4,6-trinitrophenol (TNP)-specific IgM and IgG
• following immunization with the T-independent type II antigen TNP-Ficoll or with T-dependent antigen TNP-keyhole limpet hemocyanin (KLH), produce lower amounts of antigen-specific IgM and IgG antibodies
• no high-affinity TNP-specific IgG antibodies detected after secondary immunization with TNP-KLH
• significantly reduced IgA serum level at 8 weeks old
• following immunization with the T-independent type II antigen TNP-Ficoll or with T-dependent antigen TNP-keyhole limpet hemocyanin (KLH), produce lower amounts of antigen-specific IgG antibodies
• significantly reduced IgG2b serum level at 8 weeks old
• significantly reduced IgG3 serum level at 8 weeks old
• significantly reduced IgM serum level at 8 weeks old
• following immunization with the T-independent type II antigen TNP-Ficoll or with T-dependent antigen TNP-keyhole limpet hemocyanin (KLH), produce lower amounts of antigen-specific IgM antibodies
• the vast majority of the CD4+ or CD8+ splenic T cells are CD44+ CD62L_, suggesting in vivo activation
• dramatic defect of splenic T cell proliferation, as assessed by 5,6-carboxyfluorescein succinimidyl ester (CFSE) dilution in vitro in the presence of anti-CD3 monoclonal antibody (mAb) in combination with either anti-CD28 mAb or IL-2
• reduced IFN-gamma secretion in splenic T cells
• reduced IL-13 secretion in splenic T cells
• modest inflammatory infiltrates (mainly composed of T lymphocytes and neutrophils) in the liver

liver/biliary system
• modest inflammatory infiltrates (mainly composed of T lymphocytes and neutrophils) in the liver

digestive/alimentary system
• colon adenocarcinoma in 4 out of 44 mice
• modest inflammatory infiltrates (mainly composed of T lymphocytes and neutrophils) in the gut

neoplasm
• colon adenocarcinoma in 4 out of 44 mice
• significant proportion (13/44) of them develop thymic tumors
• medulloblastoma in 1 out of 44 mice

hematopoietic system
• markedly reduced viability and increased apoptosis when simultaneously stained for annexin-V and 7-Aminoactinomycin D (7-AAD) for in vitro activated mutant splenic T cells
• mild architectural abnormalities with conserved demarcation between the cortex and the small-sized medulla
• overall preservation of the thymic architecture and of the corticomedullary demarcation
• decreased number in total thymic cellularity
• significantly reduced B220+ cells in the bone marrow
• majority of B220+ IgM- cells expressed CD43, indicating an incomplete block at the pro-B cell stage
• significantly reduced B220+ IgM+ B cells in the spleen
• a restricted repertoire of the splenic B cells
• clonal rearrangements or deletion of the Jbeta1 cluster in the vast majority of the tumors (8 of 13)
• clonal rearrangements involving the Jbeta2 cluster in several of the tumors
• a restricted T cell receptor (TCR) Vbeta repertoire in the spleen
• a largely polyclonal TCR Vbeta repertoire in the thymus
• drastically reduced absolute number of CD4_CD8_ double-negative (DN) T cell
• accumulation of DN thymocytes at the CD44_ CD25+ DN3 stage of development
• drastically reduced absolute number of CD4+ CD8+ double-positive T cell
• a lower number of transitional, follicular, and marginal zone splenic B cells
• drastically reduced absolute number of CD4+ T cell in the mutant thymus and spleen
• drastically reduced absolute number of CD8+ T cell in the mutant thymus and spleen
• CD4+ CD25hi Foxp3+ regulatory T cells in mesenteric lymph nodes
• markedly reduced total cellularity in the spleen
• spontaneously produced higher titers of 2,4,6-trinitrophenol (TNP)-specific IgM and IgG
• following immunization with the T-independent type II antigen TNP-Ficoll or with T-dependent antigen TNP-keyhole limpet hemocyanin (KLH), produce lower amounts of antigen-specific IgM and IgG antibodies
• no high-affinity TNP-specific IgG antibodies detected after secondary immunization with TNP-KLH
• significantly reduced IgA serum level at 8 weeks old
• following immunization with the T-independent type II antigen TNP-Ficoll or with T-dependent antigen TNP-keyhole limpet hemocyanin (KLH), produce lower amounts of antigen-specific IgG antibodies
• significantly reduced IgG2b serum level at 8 weeks old
• significantly reduced IgG3 serum level at 8 weeks old
• significantly reduced IgM serum level at 8 weeks old
• following immunization with the T-independent type II antigen TNP-Ficoll or with T-dependent antigen TNP-keyhole limpet hemocyanin (KLH), produce lower amounts of antigen-specific IgM antibodies
• the vast majority of the CD4+ or CD8+ splenic T cells are CD44+ CD62L_, suggesting in vivo activation
• dramatic defect of splenic T cell proliferation, as assessed by 5,6-carboxyfluorescein succinimidyl ester (CFSE) dilution in vitro in the presence of anti-CD3 monoclonal antibody (mAb) in combination with either anti-CD28 mAb or IL-2

endocrine/exocrine glands
• mild architectural abnormalities with conserved demarcation between the cortex and the small-sized medulla
• overall preservation of the thymic architecture and of the corticomedullary demarcation
• decreased number in total thymic cellularity
• significant proportion (13/44) of them develop thymic tumors

Mouse Models of Human Disease
DO ID OMIM ID(s) Ref(s)
DNA ligase IV deficiency DOID:0060021 OMIM:606593
J:157574


Contributing Projects:
Mouse Genome Database (MGD), Gene Expression Database (GXD), Mouse Models of Human Cancer database (MMHCdb) (formerly Mouse Tumor Biology (MTB), Gene Ontology (GO)
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last database update
02/16/2021
MGI 6.16
The Jackson Laboratory