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Phenotypes Associated with This Genotype
Genotype
MGI:3629514
Allelic
Composition
Tnftm2Gkl/Tnf+
Genetic
Background
involves: 129S/SvEv * C57BL/6J
Find Mice Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Tnftm2Gkl mutation (1 available); any Tnf mutation (35 available)
phenotype observed in females
phenotype observed in males
N normal phenotype
skeleton
• cultured synovial fibroblasts are bipolar rather than multipolar and exhibit a more complex and denser actin filament network

cellular
• mice display high levels of apoptosis in the ilea at 3 months of age
• valvular interstitial cells show 70-80% closure of a wound in culture compared to around 20% in wild-type cells, indicating increased migration
• synovial fibroblasts show 70-80% closure of a wound in culture compared to around 20% in wild-type cells, indicating increased migration
• valvular interstitial cells display a 2- to 3-fold increase in proliferation
• synovial fibroblasts display a 2- to 3-fold increase in proliferation

cardiovascular system
• by 16 weeks of age, the aortic root is thickened to about 10-15 times compared with wild-type
• cultured valvular interstitial cells are bipolar rather than multipolar and exhibit a more complex and denser actin filament network
• mice progressively develop stenosis of the aortic valve leaflets starting at 8 weeks of age with 100% incidence
• treatment with an anti-TNF, etanercept (enbrel), and prophylactic regimen for 10 weeks upon disease initiation prevents the development of aortic valve stenosis and fibrosis
• by 16 weeks of age, the aortic valve leaflets are thickened to about 10-15 times compared with wild-type
• thickened valves develop fibrosis but show very little immune cell infiltration
• treatment with an anti-TNF, etanercept (enbrel), and prophylactic regimen for 10 weeks upon disease initiation prevents the development of aortic valve fibrosis
• cardiac output is reduced at 4 months of age
• mice exhibit a mild, but significant, reduction in left ventricular ejection fraction
• mice exhibit a higher peak aortic valve flow
• heart rate is reduced at 4 months of age
• mice exhibit prolonged heart rate corrected time from the start of the Q wave to the end of the T wave on the ECG trace (QTc) interval prolongation

homeostasis/metabolism
• circulating TNF levels are elevated
• synovial fibroblasts and valvular interstitial cells show 70-80% closure of a wound in culture compared to around 20% in wild-type cells

immune system
• inflammatory bowel disease develops between 4-8 weeks of age
• splenocyte counts past 2 months of age show increases in CD11b+ myeloid cells
• there is a significant increase in CD8+ T cell number in Tnftm2Gkl mice past 2 months of age
• mild splenomegaly development correlates with inflammatory bowel disease (IBD) development and becomes significant by 4 months of age
• T lymphocytes show a high degree of target cell lysis of syngeneic targets
• in allogeneic mixed lymphocyte reactions, splenocytes show enhanced proliferation compared to wild-type controls
• circulating TNF levels are elevated
• levels of secreted TNF-alpha in supernatants of cultured synovial fibroblasts and valvular interstitial cells are elevated
• when lethality irradiated heterozygotes (that had also received anti-Tnf antibody treatment) receive bone marrow from wild-type mice only display mild villus blunting 9 weeks after removal of antibody treatment

hematopoietic system
• splenocyte counts past 2 months of age show increases in CD11b+ myeloid cells
• there is a significant increase in CD8+ T cell number in Tnftm2Gkl mice past 2 months of age
• mild splenomegaly development correlates with inflammatory bowel disease (IBD) development and becomes significant by 4 months of age
• T lymphocytes show a high degree of target cell lysis of syngeneic targets
• in allogeneic mixed lymphocyte reactions, splenocytes show enhanced proliferation compared to wild-type controls

muscle
• mice exhibit a mild, but significant, reduction in left ventricular ejection fraction

digestive/alimentary system
• inflammatory bowel disease develops between 4-8 weeks of age


Contributing Projects:
Mouse Genome Database (MGD), Gene Expression Database (GXD), Mouse Tumor Biology (MTB), Gene Ontology (GO), MouseCyc
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last database update
04/09/2019
MGI 6.13
The Jackson Laboratory