Phenotypes Associated with This Genotype

Genotype
MGI:3526798

• Allelic Composition: Dnase2a^tm1Osa/Dnase2a^tm1Osa; Ifnar1^tm1Agt/Ifnar1^tm1Agt
• Genetic Background: involves: 129S1/Sv * 129S2/SvPas * 129X1/SvJ * C57BL/6

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

growth/size/body

postnatal growth retardation ( J:114982 )

enlarged spleen ( J:114982 , J:238323 )

• develop splenomegaly from 1 month of age, which becomes prominent as mutants age (J:114982)

• splenomegaly, with spleen sizes being 4-5 fold increased (J:238323)

increased spleen weight ( J:238323 )

immune system

abnormal macrophage morphology ( J:114982 )

• exhibit numerous abnormal macrophages that contain DNA in lysosomes in the bone marrow, spleen and other tissues

abnormal spleen morphology ( J:238323 )

• increase in expression of IFN-beta in splenic tissue

enlarged spleen ( J:114982 , J:238323 )

• develop splenomegaly from 1 month of age, which becomes prominent as mutants age (J:114982)

• splenomegaly, with spleen sizes being 4-5 fold increased (J:238323)

increased spleen weight ( J:238323 )

increased spleen red pulp amount ( J:114982 )

• splenomegaly due to enlargement of the red pulp

abnormal cytokine level ( J:114982 )

• affected joints show 5-100 fold elevation of TNF-alpha, IL-1beta, IL-6, IL-10, IFN-beta, and IFN-gamma mRNA levels, the set of cytokines that are elevated in joints of humans with rheumatoid arthritis

increased circulating interleukin-10 level ( J:238323 )

increased circulating interleukin-18 level ( J:114982 )

• serum shows elevated levels of IL-18 protein

increased circulating tumor necrosis factor level ( J:114982 , J:238323 )

• serum shows elevated levels of TNF-alpha at 4-6 weeks of age, before joints show abnormalities; the extend of elevation decreases as mutants age (J:114982)

increased autoantibody level ( J:238323 )

• presence of anti-cyclic citrullinated peptide antibodies

increased anti-double stranded DNA antibody level ( J:114982 )

• level of anti-double-stranded DNA antibody is elevated 3-fold

joint inflammation ( J:114982 , J:238323 )

• joints of show severe synovitis with villus proliferation accompanied by pannus formation; pannus fills the joint cavity, erodes cartilage, destroys bones, and occasionally penetrates the bone marrow (J:114982)

• exhibit infiltration of subsynovial tissues by T cells and neutrophils (J:114982)

• joints show severe signs of synovitis with hyperproliferation of synovial cells and massive immune cell infiltration at 15 months of age, associated with panus formation, cartilage destruction, and bone erosion (J:238323)

rheumatoid arthritis ( J:114982 , J:238323 )

• develop polyarthritis as age; forelimbs and hindlimbs begin to swell at 2-3 months of age and swelling first affects the digits, then the foot and finally the wrists and ankles (J:114982)

• mice develop chronic polyarthritis that progresses with age (J:238323)

• joints show an increase in cleaved caspase-1, indicating signs of inflammasome activation (J:238323)

• expression of pro-inflammatory cytokines such as TNF, IL-6, and IL-1beta is increased both at protein and mRNA level in joints (J:238323)

• immune cell infiltrate is mainly dominated by presence of macrophages (J:238323)

hematopoietic system

anemia ( J:114982 )

• slightly anemic

abnormal macrophage morphology ( J:114982 )

• exhibit numerous abnormal macrophages that contain DNA in lysosomes in the bone marrow, spleen and other tissues

abnormal spleen morphology ( J:238323 )

• increase in expression of IFN-beta in splenic tissue

enlarged spleen ( J:114982 , J:238323 )

• develop splenomegaly from 1 month of age, which becomes prominent as mutants age (J:114982)

• splenomegaly, with spleen sizes being 4-5 fold increased (J:238323)

increased spleen weight ( J:238323 )

increased spleen red pulp amount ( J:114982 )

• splenomegaly due to enlargement of the red pulp

homeostasis/metabolism

abnormal blood homeostasis ( J:114982 )

• carry a significant level of DNA in serum which decreases as mutants age

abnormal cytokine level ( J:114982 )

• affected joints show 5-100 fold elevation of TNF-alpha, IL-1beta, IL-6, IL-10, IFN-beta, and IFN-gamma mRNA levels, the set of cytokines that are elevated in joints of humans with rheumatoid arthritis

increased circulating interleukin-10 level ( J:238323 )

increased circulating interleukin-18 level ( J:114982 )

• serum shows elevated levels of IL-18 protein

increased circulating tumor necrosis factor level ( J:114982 , J:238323 )

• serum shows elevated levels of TNF-alpha at 4-6 weeks of age, before joints show abnormalities; the extend of elevation decreases as mutants age (J:114982)

skeleton

joint inflammation ( J:114982 , J:238323 )

• joints of show severe synovitis with villus proliferation accompanied by pannus formation; pannus fills the joint cavity, erodes cartilage, destroys bones, and occasionally penetrates the bone marrow (J:114982)

• exhibit infiltration of subsynovial tissues by T cells and neutrophils (J:114982)

• joints show severe signs of synovitis with hyperproliferation of synovial cells and massive immune cell infiltration at 15 months of age, associated with panus formation, cartilage destruction, and bone erosion (J:238323)

rheumatoid arthritis ( J:114982 , J:238323 )

• develop polyarthritis as age; forelimbs and hindlimbs begin to swell at 2-3 months of age and swelling first affects the digits, then the foot and finally the wrists and ankles (J:114982)

• mice develop chronic polyarthritis that progresses with age (J:238323)

• joints show an increase in cleaved caspase-1, indicating signs of inflammasome activation (J:238323)

• expression of pro-inflammatory cytokines such as TNF, IL-6, and IL-1beta is increased both at protein and mRNA level in joints (J:238323)

• immune cell infiltrate is mainly dominated by presence of macrophages (J:238323)

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
rheumatoid arthritis		DOID:7148	OMIM:180300	J:114982 , J:238323