Phenotypes Associated with This Genotype

Genotype
MGI:2654203

• Allelic Composition: Trp53bp1^tm1Jc/Trp53bp1^tm1Jc
• Genetic Background: involves: 129 * C57BL/6

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

mortality/aging

increased mortality induced by ionizing radiation ( J:82512 )

• in response to 8 Gy of whole body ionizing radiation (IR), all homozygotes die by 14 days from radiation-induced intestinal bleeding and bone marrow failure, whereas most wild-type mice remain viable for at least 2 months after IR treatment

premature death ( J:82512 )

• 9% of homozygotes die at the ages of 1 to 7 months in the absence of overt detectable tumors; possibly due to opportunistic infections

growth/size/body

decreased body size ( J:82512 )

• homozygotes are significantly smaller than wild-type and heterozygous control mice

decreased body weight ( J:82512 )

• at 5 months of age, both male and female homozygotes weigh significantly less than their wild-type or heterozygous counterparts

postnatal growth retardation ( J:82512 )

• homozygotes of both sexes are growth retarded relative to wild-type or heterozygous control littermates

immune system

thymus hypoplasia ( J:82512 )

• homozygotes show a 40% reduction in thymus cellularity relative to wild-type littermates

increased double-negative T cell number ( J:82512 )

• at 6 weeks of age, homozygotes show a maximum 2-fold increase in the percentage of CD4^- CD8^- progenitors relative to wild-type littermates

decreased CD4-positive, alpha-beta T cell number ( J:82512 )

• at 6 weeks of age, homozygotes show a ~2-fold reduction in the percentage of CD4⁺ mature thymocytes and peripheral CD4⁺ T lymphocytes relative to wild-type littermates

hematopoietic system

thymus hypoplasia ( J:82512 )

• homozygotes show a 40% reduction in thymus cellularity relative to wild-type littermates

increased double-negative T cell number ( J:82512 )

• at 6 weeks of age, homozygotes show a maximum 2-fold increase in the percentage of CD4^- CD8^- progenitors relative to wild-type littermates

decreased CD4-positive, alpha-beta T cell number ( J:82512 )

• at 6 weeks of age, homozygotes show a ~2-fold reduction in the percentage of CD4⁺ mature thymocytes and peripheral CD4⁺ T lymphocytes relative to wild-type littermates

cellular

aneuploidy ( J:82512 )

• mutant MEFs (passage 3) show a tendency toward aneuploidy

abnormal cell cycle checkpoint function ( J:82512 )

• several hrs after exposure to 6 Gy of ionizing radiation (IR), mutant MEFs, like wild-type MEFs, are arrested in G₂ but display a delayed exit from the G₂/M phase

• at 24 hrs after IR, the % of mitotic cells is ~3-fold lower in nocodazole-treated mutant MEFs than in wild-type cells, as assessed by immunostaining with anti-phospho-histone H3 antibodies

• at 30 min after exposure to 20 Gy of IR, mutant MEFs show a slight defect in intra-S-phase checkpoint regulation relative to wild-type MEFs

• however, mutant MEFs, synchronized by a cycle of serum starvation and release, show a normal G₁ arrest in response to 10 to 20 Gy of IR

increased cellular sensitivity to ionizing radiation ( J:82512 )

• mutant ES cells show a 2- to 3-fold increase in ionizing radiation sensitivity relative to wild-type ES cells, revealed by in vitro clonogenic survival assays

decreased cell proliferation ( J:82512 )

• MEFs derived from E14.5 homozygous mutant embryos display a reduced proliferation rate relative to wild-type MEFs

chromosomal instability ( J:82512 )

• mutant MEFs (passage 3) show a tendency toward aneuploidy and/or tetraploidy, suggesting a defect in chromosome segregation

• however, no spontaneous chromosomal breaks are detected in mutant MEFs

neoplasm

increased lymphoma incidence ( J:82512 )

• homozygotes exhibit an increased incidence of malignant lymphomas, putatively due to an inability to detect or repair abnormal V(D)J recombination

increased T cell derived lymphoma incidence ( J:82512 )

• at 4 to 7 months of age, 8% of homozygotes develop massive thymic lymphomas with or without infiltration of the lymph nodes, spleen, and kidney, not observed in wild-type or heterozygous control mice

• three of these tumors display a CD4⁺ CD8⁺ immunophenotype

reproductive system

reproductive system phenotype ( J:82512 )

N • male homozygotes show no overt defects in spermatogenesis, suggesting normal meiosis

decreased litter size ( J:82512 )

• although both male and female homozygotes are fertile, the average litter size of homozygous mutant intercrosses is slightly reduced relative to that of wild-type intercrosses

homeostasis/metabolism

increased mortality induced by ionizing radiation ( J:82512 )

• in response to 8 Gy of whole body ionizing radiation (IR), all homozygotes die by 14 days from radiation-induced intestinal bleeding and bone marrow failure, whereas most wild-type mice remain viable for at least 2 months after IR treatment

endocrine/exocrine glands

thymus hypoplasia ( J:82512 )

• homozygotes show a 40% reduction in thymus cellularity relative to wild-type littermates

increased T cell derived lymphoma incidence ( J:82512 )

• three of these tumors display a CD4⁺ CD8⁺ immunophenotype

• at 4 to 7 months of age, 8% of homozygotes develop massive thymic lymphomas with or without infiltration of the lymph nodes, spleen, and kidney, not observed in wild-type or heterozygous control mice