Phenotypes Associated with This Genotype

Genotype
MGI:3629514

• Allelic Composition: Tnf^tm2Gkl/Tnf⁺
• Genetic Background: involves: 129S/SvEv * C57BL/6J

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

skeleton

abnormal joint morphology ( J:264147 )

• cultured synovial fibroblasts are bipolar rather than multipolar and exhibit a more complex and denser actin filament network

cellular

increased apoptosis ( J:108572 )

• mice display high levels of apoptosis in the ilea at 3 months of age

increased cell migration ( J:264147 )

• valvular interstitial cells show 70-80% closure of a wound in culture compared to around 20% in wild-type cells, indicating increased migration

increased fibroblast cell migration ( J:264147 )

• synovial fibroblasts show 70-80% closure of a wound in culture compared to around 20% in wild-type cells, indicating increased migration

increased cell proliferation ( J:264147 )

• valvular interstitial cells display a 2- to 3-fold increase in proliferation

increased fibroblast proliferation ( J:264147 )

• synovial fibroblasts display a 2- to 3-fold increase in proliferation

cardiovascular system

abnormal aorta bulb morphology ( J:264147 )

• by 16 weeks of age, the aortic root is thickened to about 10-15 times compared with wild-type

abnormal aortic valve morphology ( J:264147 )

• cultured valvular interstitial cells are bipolar rather than multipolar and exhibit a more complex and denser actin filament network

thick aortic valve cusps ( J:264147 )

• by 16 weeks of age, the aortic valve leaflets are thickened to about 10-15 times compared with wild-type

aortic valve stenosis ( J:264147 )

• 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

cardiac fibrosis ( J:264147 )

• 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

decreased cardiac output ( J:264147 )

• cardiac output is reduced at 4 months of age

decreased heart left ventricle muscle contractility ( J:264147 )

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

abnormal aortic valve flow ( J:264147 )

• mice exhibit a higher peak aortic valve flow

decreased heart rate ( J:264147 )

• heart rate is reduced at 4 months of age

prolonged QT interval ( J:264147 )

• 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

increased circulating tumor necrosis factor level ( J:264147 )

• circulating TNF levels are elevated

enhanced wound healing ( J:264147 )

• 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

small intestinal inflammation ( J:108572 )

• inflammatory bowel disease develops between 4-8 weeks of age

enlarged spleen ( J:108572 )

• mild splenomegaly development correlates with inflammatory bowel disease (IBD) development and becomes significant by 4 months of age

abnormal myelopoiesis ( J:108572 )

• splenocyte counts past 2 months of age show increases in CD11b+ myeloid cells

increased CD8-positive, alpha-beta T cell number ( J:108572 )

• there is a significant increase in CD8+ T cell number in Tnf^tm2Gkl mice past 2 months of age

abnormal cytotoxic T cell physiology ( J:108572 )

• 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

increased circulating tumor necrosis factor level ( J:264147 )

• circulating TNF levels are elevated

increased tumor necrosis factor secretion ( J:264147 )

• levels of secreted TNF-alpha in supernatants of cultured synovial fibroblasts and valvular interstitial cells are elevated

abnormal response to transplant ( J:108572 )

• 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

enlarged spleen ( J:108572 )

• mild splenomegaly development correlates with inflammatory bowel disease (IBD) development and becomes significant by 4 months of age

abnormal myelopoiesis ( J:108572 )

• splenocyte counts past 2 months of age show increases in CD11b+ myeloid cells

increased CD8-positive, alpha-beta T cell number ( J:108572 )

• there is a significant increase in CD8+ T cell number in Tnf^tm2Gkl mice past 2 months of age

abnormal cytotoxic T cell physiology ( J:108572 )

• 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

decreased heart left ventricle muscle contractility ( J:264147 )

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

digestive/alimentary system

small intestinal inflammation ( J:108572 )

• inflammatory bowel disease develops between 4-8 weeks of age

growth/size/body

enlarged spleen ( J:108572 )

• mild splenomegaly development correlates with inflammatory bowel disease (IBD) development and becomes significant by 4 months of age

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
aortic valve stenosis		DOID:1712		J:264147
rheumatoid arthritis		DOID:7148	OMIM:180300	J:264147
spondyloarthropathy		DOID:1123		J:264147