Phenotypes Associated with This Genotype

Genotype
MGI:6195613

cx2

• Allelic Composition: Tnf^tm2Gkl/Tnf⁺; Tnfrsf1b^tm1.2Gkl/Tnfrsf1b^tm1.2Gkl
• Genetic Background: involves: 129S/SvEv * C57BL/6 * C57BL/6J

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

cardiovascular system

aortic valve stenosis ( J:264147 )

• mice exhibit an exacerbated aortic valve stenosis than seen in single Tnf^tm2Gkl heterozygotes, with an increase of valve leaflet surface area and fibrosis

• disease-manifestation in heart valve leaflets occurs at earlier time points than in single Tnf^tm2Gkl heterozygotes

• an increase of T and B cell infiltration is seen in late stages of the disease in the aortic valve leaflets compared to single Tnf^tm2Gkl heterozygotes

cardiac fibrosis ( J:264147 )

• mice exhibit exacerbated aortic valve fibrosis compared to in single Tnf^tm2Gkl heterozygotes

aortic valve inflammation ( J:264147 )

• an increase of T and B cell infiltration is seen in late stages of the disease in the aortic valve leaflets compared to single Tnf^tm2Gkl heterozygotes

skeleton

autoimmune arthritis ( J:264147 )

• mice exhibit a more aggressive and destructive type of arthritis, exacerbated synovial hyperplasia, and bone destruction compared to single Tnf^tm2Gkl heterozygotes

• disease-manifestation in joints occurs at earlier time points than in single Tnf^tm2Gkl heterozygotes

• an increase of T and B cell infiltration is seen in late stages of the disease in the ankle joint compared to single Tnf^tm2Gkl heterozygotes

cellular

abnormal cell physiology ( J:264147 )

• valvular interstitial cells fail to become activated

• however, cultured valvular interstitial cells appear similar to wild-type cells and exhibit normal proliferation

abnormal cell adhesion ( J:264147 )

• synovial fibroblast and valvular interstitial cell adhesion to a fibronectin substrate is reduced by almost 50% compared to the levels in single Tnf^tm2Gkl heterozygotes but is higher than in wild-type cells

abnormal fibroblast physiology ( J:264147 )

• synovial fibroblasts fail to become activated

• however, cultured synovial fibroblasts appear similar to wild-type cells and exhibit normal proliferation

homeostasis/metabolism

increased circulating tumor necrosis factor level ( J:264147 )

• circulating TNF levels are elevated

abnormal wound healing ( J:264147 )

• synovial fibroblasts and valvular interstitial cells show only 40-45% closure of a wound in culture compared to 70-80% closure in single Tnf^tm2Gkl heterozygotes and about 20% closure in wild-type cells

immune system

aortic valve inflammation ( J:264147 )

• an increase of T and B cell infiltration is seen in late stages of the disease in the aortic valve leaflets compared to single Tnf^tm2Gkl heterozygotes

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

autoimmune arthritis ( J:264147 )

• mice exhibit a more aggressive and destructive type of arthritis, exacerbated synovial hyperplasia, and bone destruction compared to single Tnf^tm2Gkl heterozygotes

• disease-manifestation in joints occurs at earlier time points than in single Tnf^tm2Gkl heterozygotes

• an increase of T and B cell infiltration is seen in late stages of the disease in the ankle joint compared to single Tnf^tm2Gkl heterozygotes