Phenotypes associated with this allele

• Allele Symbol: Lig4^tm2.1Fwa
• Allele Name: targeted mutation 2.1, Frederick W Alt
• Allele ID: MGI:4437270
• Summary: 1 genotype

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Lig4^tm2.1Fwa/Lig4^tm2.1Fwa	involves: 129S6/SvEvTac	MGI:4437271

Genotype
MGI:4437271

hm1

• Allelic Composition: Lig4^tm2.1Fwa/Lig4^tm2.1Fwa
• Genetic Background: involves: 129S6/SvEvTac

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

mortality/aging

premature death ( J:157574 )

• reduced life span

growth/size/body

decreased body size ( J:157574 )

• reduced body size at birth, 4 and 20 weeks of age

decreased body weight ( J:157574 )

• reduced body weight at 4 and 20 weeks of age

postnatal growth retardation ( J:157574 )

• growth retardation at 4 months of age

cellular

abnormal cell physiology ( J:157574 )

• 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

increased cellular sensitivity to gamma-irradiation ( J:157574 )

• increased radiation sensitivity in mutant mouse embryonic fibroblasts

increased T cell apoptosis ( J:157574 )

• 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

decreased T cell proliferation ( J:157574 )

• 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

chromosomal instability ( J:157574 )

• 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

spontaneous chromosome breakage ( J:157574 )

reproductive system

reduced fertility ( J:157574 )

• fertility of mutant mice is severely compromised

immune system

abnormal immune system morphology ( J:157574 )

abnormal immune system cell morphology ( J:157574 )

abnormal B cell differentiation ( J:157574 )

• 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

abnormal T cell differentiation ( J:157574 )

abnormal T cell receptor V(D)J recombination ( J:157574 )

• 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

abnormal T cell receptor beta chain V(D)J recombination ( J:157574 )

• a restricted T cell receptor (TCR) Vbeta repertoire in the spleen

• a largely polyclonal TCR Vbeta repertoire in the thymus

decreased double-negative T cell number ( J:157574 )

• drastically reduced absolute number of CD4_CD8_ double-negative (DN) T cell

• accumulation of DN thymocytes at the CD44_ CD25+ DN3 stage of development

decreased double-positive T cell number ( J:157574 )

• drastically reduced absolute number of CD4+ CD8+ double-positive T cell

abnormal lymphocyte cell number ( J:157574 )

decreased B cell number ( J:157574 )

• a lower number of transitional, follicular, and marginal zone splenic B cells

decreased CD4-positive, alpha-beta T cell number ( J:157574 )

• drastically reduced absolute number of CD4+ T cell in the mutant thymus and spleen

decreased CD8-positive, alpha-beta T cell number ( J:157574 )

• drastically reduced absolute number of CD8+ T cell in the mutant thymus and spleen

abnormal regulatory T cell morphology ( J:157574 )

• CD4+ CD25hi Foxp3+ regulatory T cells in mesenteric lymph nodes

abnormal immune system organ morphology ( J:157574 )

abnormal thymus morphology ( J:157574 )

• 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

small thymus ( J:157574 )

decreased thymus weight ( J:157574 )

decreased thymocyte number ( J:157574 )

• decreased number in total thymic cellularity

increased T cell derived lymphoma incidence ( J:157574 )

• significant proportion (13/44) of them develop thymic tumors

small spleen ( J:157574 )

decreased spleen weight ( J:157574 )

decreased splenocyte number ( J:157574 )

• markedly reduced total cellularity in the spleen

abnormal immune system physiology ( J:157574 )

increased T cell apoptosis ( J:157574 )

• 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

intestinal inflammation ( J:157574 )

• modest inflammatory infiltrates (mainly composed of T lymphocytes and neutrophils) in the gut

abnormal B cell activation ( J:157574 )

• 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

decreased immunoglobulin level ( J:157574 )

decreased IgA level ( J:157574 )

• significantly reduced IgA serum level at 8 weeks old

decreased IgG level ( J:157574 )

• 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

decreased IgG2b level ( J:157574 )

• significantly reduced IgG2b serum level at 8 weeks old

decreased IgG3 level ( J:157574 )

• significantly reduced IgG3 serum level at 8 weeks old

decreased IgM level ( J:157574 )

• 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

abnormal T cell activation ( J:157574 )

• the vast majority of the CD4+ or CD8+ splenic T cells are CD44+ CD62L_, suggesting in vivo activation

decreased T cell proliferation ( J:157574 )

• 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

decreased interferon-gamma secretion ( J:157574 )

• reduced IFN-gamma secretion in splenic T cells

decreased interleukin-13 secretion ( J:157574 )

• reduced IL-13 secretion in splenic T cells

increased anti-chromatin antibody level ( J:157574 )

increased anti-double stranded DNA antibody level ( J:157574 )

liver inflammation ( J:157574 )

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

liver/biliary system

liver inflammation ( J:157574 )

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

digestive/alimentary system

increased colon adenocarcinoma incidence ( J:157574 )

• colon adenocarcinoma in 4 out of 44 mice

intestinal inflammation ( J:157574 )

• modest inflammatory infiltrates (mainly composed of T lymphocytes and neutrophils) in the gut

neoplasm

increased colon adenocarcinoma incidence ( J:157574 )

• colon adenocarcinoma in 4 out of 44 mice

increased T cell derived lymphoma incidence ( J:157574 )

• significant proportion (13/44) of them develop thymic tumors

increased medulloblastoma incidence ( J:157574 )

• medulloblastoma in 1 out of 44 mice

hematopoietic system

increased T cell apoptosis ( J:157574 )

• 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

abnormal thymus morphology ( J:157574 )

• 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

small thymus ( J:157574 )

decreased thymus weight ( J:157574 )

decreased thymocyte number ( J:157574 )

• decreased number in total thymic cellularity

increased T cell derived lymphoma incidence ( J:157574 )

• significant proportion (13/44) of them develop thymic tumors

abnormal B cell differentiation ( J:157574 )

• 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

abnormal T cell differentiation ( J:157574 )

abnormal T cell receptor V(D)J recombination ( J:157574 )

• 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

abnormal T cell receptor beta chain V(D)J recombination ( J:157574 )

• a restricted T cell receptor (TCR) Vbeta repertoire in the spleen

• a largely polyclonal TCR Vbeta repertoire in the thymus

decreased double-negative T cell number ( J:157574 )

• drastically reduced absolute number of CD4_CD8_ double-negative (DN) T cell

• accumulation of DN thymocytes at the CD44_ CD25+ DN3 stage of development

decreased double-positive T cell number ( J:157574 )

• drastically reduced absolute number of CD4+ CD8+ double-positive T cell

abnormal lymphocyte cell number ( J:157574 )

decreased B cell number ( J:157574 )

• a lower number of transitional, follicular, and marginal zone splenic B cells

decreased CD4-positive, alpha-beta T cell number ( J:157574 )

• drastically reduced absolute number of CD4+ T cell in the mutant thymus and spleen

decreased CD8-positive, alpha-beta T cell number ( J:157574 )

• drastically reduced absolute number of CD8+ T cell in the mutant thymus and spleen

abnormal regulatory T cell morphology ( J:157574 )

• CD4+ CD25hi Foxp3+ regulatory T cells in mesenteric lymph nodes

small spleen ( J:157574 )

decreased spleen weight ( J:157574 )

decreased splenocyte number ( J:157574 )

• markedly reduced total cellularity in the spleen

abnormal B cell activation ( J:157574 )

• 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

decreased immunoglobulin level ( J:157574 )

decreased IgA level ( J:157574 )

• significantly reduced IgA serum level at 8 weeks old

decreased IgG level ( J:157574 )

• 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

decreased IgG2b level ( J:157574 )

• significantly reduced IgG2b serum level at 8 weeks old

decreased IgG3 level ( J:157574 )

• significantly reduced IgG3 serum level at 8 weeks old

decreased IgM level ( J:157574 )

• 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

abnormal T cell activation ( J:157574 )

• the vast majority of the CD4+ or CD8+ splenic T cells are CD44+ CD62L_, suggesting in vivo activation

decreased T cell proliferation ( J:157574 )

• 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

abnormal thymus morphology ( J:157574 )

• 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

small thymus ( J:157574 )

decreased thymus weight ( J:157574 )

decreased thymocyte number ( J:157574 )

• decreased number in total thymic cellularity

increased T cell derived lymphoma incidence ( J:157574 )

• significant proportion (13/44) of them develop thymic tumors

nervous system

increased medulloblastoma incidence ( J:157574 )

• medulloblastoma in 1 out of 44 mice

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