Mouse Genome Informatics
hm1
    Tnftm1Gkl/Tnftm1Gkl
B6;129S-Tnftm1Gkl/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
reproductive system
• at 12 weeks of age, male homozygotes show a ~30% reduction in average testis weight relative to wild-type controls (J:143457)
• after puberty (P30 to adulthood), mRNA levels of key steroidogenesis-related genes are significantly lower in mutant testes than in wild-type testes (J:143457)
• after puberty, male homozygotes display significantly lower testicular testosterone levels than wild-type males, as a result of higher anti-Mullerian hormone levels in mutant testes (J:143457)
• male homozygotes show a significant delay in the onset of spermatogenesis, likely due to decreased testicular testosterone levels (J:143457)
• at P26, the most advanced germ cells in mutant testes remain as late pachytene spermatocytes, instead of developing into haploid round spermatids as in wild-type testes (J:143457)
• at P33, only early elongated spermatids are noted in mutant testes, whereas late elongated spermatids are seen in wild-type testes (J:143457)
• at 12 weeks of age, male homozygotes show a ~53% reduction in epididymal sperm count relative to wild-type controls (J:143457)
• in mutant males, the number of sperm per testis weight is only ~68% that of wild-type controls (J:143457)
• at P37, no sperm are yet detected in mutant epididymides (J:143457)
• at P56, spermatozoa are detected at the luminal edge of seminiferous epithelia in both wild-type and mutant testes; however, the lumen is only dilated in wild-type tubules indicating active release of sperm (J:143457)

endocrine/exocrine glands
• at 12 weeks of age, male homozygotes show a ~30% reduction in average testis weight relative to wild-type controls (J:143457)
• after puberty (P30 to adulthood), mRNA levels of key steroidogenesis-related genes are significantly lower in mutant testes than in wild-type testes (J:143457)
• after puberty, male homozygotes display significantly lower testicular testosterone levels than wild-type males, as a result of higher anti-Mullerian hormone levels in mutant testes (J:143457)


Mouse Genome Informatics
hm2
    Tnftm1Gkl/Tnftm1Gkl
C.129S-Tnftm1Gkl
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
tumorigenesis
• DMBA and TPA-treated mice exhibit papillomas than in similarly treated wild-type mice

homeostasis/metabolism
• DMBA and TPA-treated mice exhibit papillomas than in similarly treated wild-type mice


Mouse Genome Informatics
hm3
    Tnftm1Gkl/Tnftm1Gkl
either: B6.129-Tnftm1Gkl or (involves: 129/Sv * C57BL/6)
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• a modest increase in peripheral white cell count is seen compared to wild-type mice
• neutrophil numbers are increased compared to Tnftm1.2Sned homozygotes
• lymphocyte numbers are increased compared to Tnftm1.2Sned homozygotes
• Peyer's patches are fewer in number
• homozygotes are protected from LPS/D-Gal induced shock
• homozygotes show increased sensitivity to systemic and alimentary L. monocytogenes infection

hematopoietic system
• a modest increase in peripheral white cell count is seen compared to wild-type mice
• neutrophil numbers are increased compared to Tnftm1.2Sned homozygotes
• lymphocyte numbers are increased compared to Tnftm1.2Sned homozygotes


Mouse Genome Informatics
hm4
    Tnftm1Gkl/Tnftm1Gkl
involves: 129S/SvEv
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• serum TNF levels were reduced in mutants injected with LPS and could not be detected on day 2 of Listeria monocytogenes infection
• induction of MCP-1 was reduced in spleens of mutants infected with Listeria monocytogenes
• increased resistance to liver injury after ConA-induced autoimmune hepatitis, with only infiltrating cells but no liver necrosis detected
• protected from S. aureus enterotoxin B induced toxic shock
• loss of resistance against Listeria monocytogenes infection

homeostasis/metabolism
• serum TNF levels were reduced in mutants injected with LPS and could not be detected on day 2 of Listeria monocytogenes infection


Mouse Genome Informatics
hm5
    Tnftm1Gkl/Tnftm1Gkl
involves: 129S/SvEv * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
growth/size/body
• at 28 weeks, mutant animals weigh less

adipose tissue

homeostasis/metabolism
• decreased plasma leptin concentrations at 28 weeks of age
• decreased fasting plasma glucose concentrations at 28 weeks of age
• decreased plasma insulin concentrations at 28 weeks of age
• decreased plasma triglyceride concentrations at 28 weeks of age
• DMBA and TPA-treated mice exhibit papillomas that develop with a greater latency than in similarly treated wild-type mice DMBA and TPA-treated mice exhibit papillomas that develop with a greater latency than in similarly treated wild-type mice however, malignant progression of tumors is normal
• however, malignant progression of tumors is normal

immune system
N
• mutant spleen cells isolated 49 days after myelin oligodendrocyte glycoprotein (MOG) display lack of autoimmune T cell responses (proliferation) to MOG peptide, similar to wild-type spleen cells (J:114740)
• organized follicular dendritic cell networks are absent
• absence of splenic primary B cell follicles
• inability to form organized germinal centers (J:47673)
• after immunization with sheep red blood cells (SRBCs), mutants fail to form organized germinal centers (J:114740)
• after intraperitoneal injection of SRBC, mutants exhibit severely impaired SRBC-specific IgG1 antibody responses
• LPS-stimulated thioglycollate-elicited peritoneal macrophages (TEPMs) cannot induce thymocyte proliferation, but stimulated TEPMs in wild-type and Tnf homozygotes induce thymocyte proliferation with equal efficiency
• organized follicular dendritic cell networks are absent
• the typical subepithelial dome areas fail to form
• B cells are present but no organized follicles are seen and organized follicular dendritic cell networks are absent
• average of 2 - 4 per mouse compared to 6 - 8 in wild-type mice
• mesenteric lymph nodes (MLN) lack organized B cell follicles but occasionally have GC-like regions that are centered in B cell areas
• B cell follicles and follicular dendritic cell network formation are impaired in mesenteric and peripheral lymph nodes; however, B cells are present and B and T cell areas are segregated
• 16 days post-immunization with pertussis toxin, mutants begin to show clinical signs of experimental allergic encephalomyelitis (EAE) which progresses to chronic non-remitting disease compared to wild-type mice which show signs of EAE at 12 days post-injectiona and peak EAE occurs at ~15 days, with gradual remission and results in only a mild deficit
• when treated with D-gal (a hepatotoxin) at 20 mg/animal and doses of lipopolysaccharide (LPS) up to 100ug/25g body weight, mutants are completely resistant to LPS-induced death, but wild-type mice all die at 100-fold lower LPS doses
• in the skin following treatment with TPA compared with similarly treated wild-type mice
• impaired contact hypersensitivity response
• susceptibility to death from Listeria monocytogenes infection (J:47673)
• with challenge at high doses (10000 cfu) of Listeria monocytogenes (LM), mutants show high sensitivity with maximal lethality at 6 days post-infection, compared to wild-type; mutants are highly sensitive when challenged with a physiological dose of LM (100 cfu) compared to wild-type (J:114740)

hematopoietic system
• organized follicular dendritic cell networks are absent
• absence of splenic primary B cell follicles
• inability to form organized germinal centers (J:47673)
• after immunization with sheep red blood cells (SRBCs), mutants fail to form organized germinal centers (J:114740)
• after intraperitoneal injection of SRBC, mutants exhibit severely impaired SRBC-specific IgG1 antibody responses
• LPS-stimulated thioglycollate-elicited peritoneal macrophages (TEPMs) cannot induce thymocyte proliferation, but stimulated TEPMs in wild-type and Tnf homozygotes induce thymocyte proliferation with equal efficiency

tumorigenesis
• DMBA and TPA-treated mice exhibit papillomas that develop with a greater latency than in similarly treated wild-type mice DMBA and TPA-treated mice exhibit papillomas that develop with a greater latency than in similarly treated wild-type mice however, malignant progression of tumors is normal
• however, malignant progression of tumors is normal

craniofacial
• modest alveolar bone loss at 30 weeks

skeleton
• modest alveolar bone loss at 30 weeks
• significantly increased
• 32% increase in trabecular bone volume

integument
• following DMBA and TPA treatment compared with similarly treated wild-type mice

cellular
• following DMBA and TPA treatment compared with similarly treated wild-type mice


Mouse Genome Informatics
hm6
    Tnftm1Gkl/Tnftm1Gkl
involves: 129S/SvEv * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• there are almost no metallophillic macrophages present in the marginal zone
• upon immunization with a T cell dependent antigen, there is a no formation of a follicular dendritic cell network
• B cells fail to form a defined primary follicle instead forming a ring-like structure that is partially mixed with the T cell region
• upon immunization with T cell dependent antigen, germinal centers fail to develop
• marginal sinus lining cells expressing mucosal addressin cell adhesion molecules are not present when immunized with a T cell antigen
• Peyer's patches have a flattened appearance
• B cells fail to segregate from T cell areas
• T cells fail to segregate from B cells
• upon immunization with a T cell dependent antigen, germinal centers fail to develop
• the mean number of Peyer's patches in mutant mice is 5 compared to 7 in wild-type mice
• 7 days after a sublethal dose of Listeria monocytogenes, no mice survive compared to 60% survival of wild-type mice

hematopoietic system
• there are almost no metallophillic macrophages present in the marginal zone
• upon immunization with a T cell dependent antigen, there is a no formation of a follicular dendritic cell network
• B cells fail to form a defined primary follicle instead forming a ring-like structure that is partially mixed with the T cell region
• upon immunization with T cell dependent antigen, germinal centers fail to develop
• marginal sinus lining cells expressing mucosal addressin cell adhesion molecules are not present when immunized with a T cell antigen


Mouse Genome Informatics
ht7
    Tnftm1Gkl/Tnftm2Gkl
involves: 129S/SvEv * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• at 6 weeks of age circulating levels of TNF are up between 90 and 430 pg/ml compared to undetectable levels in wild-type mice
• increased basal and LPS-induced secretion of TNF from thioglycollate-elicited peritoneal macrophages and bone marrow-derived macrophages
• spleen derived T lymphocytes have 3-fold greater TNF production and prolonged mRNA accumulation after incubation with an agonistic anti-CD3 antibody
• splenic B220+ cells also show increased basal and mitogen-stimulated TNF production
• primary synovial and lung fibroblasts display spontaneous TNF secretion and increased secretion following LPS stimulation unlike controls
• disease onset occurs at 6-8 weeks of age
• early signs include hyperplasia of the synovial membrane and the presence of polymorphonuclear infiltrates; progressing to pannus and fibrous tissue formation, subchondral bone erosion, and articular cartilage destruction
• both IgM and IgG are detected in arthritic joints
• increased sensitivity to LPS-induced mortality with 5 of 10 dying after injection of 100 ug/ 25 g compared to complete survival of control mice at the same dose

skeleton
• disease onset occurs at 6-8 weeks of age
• early signs include hyperplasia of the synovial membrane and the presence of polymorphonuclear infiltrates; progressing to pannus and fibrous tissue formation, subchondral bone erosion, and articular cartilage destruction
• both IgM and IgG are detected in arthritic joints

homeostasis/metabolism
• at 6 weeks of age circulating levels of TNF are up between 90 and 430 pg/ml compared to undetectable levels in wild-type mice

Mouse Models of Human Disease
OMIM IDRef(s)
Rheumatoid Arthritis; RA 180300 J:54056


Mouse Genome Informatics
cn8
    Faddtm1Mpa/Faddtm1Mpa
Tnftm1Gkl/Tnftm1Gkl
Tg(Vil-cre)997Gum/0

B6.Cg-Faddtm1Mpa Tnftm1Gkl Tg(Vil-cre)997Gum
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
digestive/alimentary system
• less severe than in Faddtm1Mpa/Faddtm1Mpa Tg(Vil-cre)997Gum mice

endocrine/exocrine glands

immune system
• less severe than in Faddtm1Mpa/Faddtm1Mpa Tg(Vil-cre)997Gum mice


Mouse Genome Informatics
cx9
    Timp3tm1Rkho/Timp3tm1Rkho
Tnftm1Gkl/Tnftm1Gkl

involves: 129 * 129S/SvEv * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• double mutants subjected to cardiac pressure overload show a greater increase in left ventricle dilation after 3 weeks than wildtype but less than seen in single Timp3 homozygous mutants
• double mutants subjected to cardiac pressure overload show a greater decline in cardiac contractility than wild-type but not as much as single Timp3 homozygous mutants

hematopoietic system
• myocardium of double mutants subjected to cardiac pressure overload contains significantly higher numbers of neutrophils scattered throughout the left ventricle compared with single homozygous Timp3 mutants or wild-type

immune system
• myocardium of double mutants subjected to cardiac pressure overload contains significantly higher numbers of neutrophils scattered throughout the left ventricle compared with single homozygous Timp3 mutants or wild-type

muscle
• double mutants subjected to cardiac pressure overload show a greater decline in cardiac contractility than wild-type but not as much as single Timp3 homozygous mutants


Mouse Genome Informatics
cx10
    Krt8tm1Rgo/Krt8tm1Rgo
Tnftm1Gkl/Tnftm1Gkl

involves: 129S/SvEv * 129S2/SvPas * C57BL/6 * FVB/N
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
N
• about 60% survive beyond 250 days (J:121811)
• Background Sensitivity: about 50% survive to birth as opposed to 25% when maternal TNF is produced


Mouse Genome Informatics
cx11
    Sh3bp2tm1Bjro/Sh3bp2tm1Bjro
Tnftm1Gkl/Tnftm1Gkl

involves: 129S/SvEv * 129S4/SvJae * BALB/cJ * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
skeleton
N
• unlike in mice homozygous for the Sh3bp2 allele alone, trabecular and cortical bone loss are not seen (J:117880)
• bone marrow displays enhanced production of osteoclasts in response to cytokine stimulation, similar to mice homozygous for the Sh3bp2 allele alone

immune system
N
• unlike in mice homozygous for the Sh3bp2 allele alone, lymph node abnormalities and systemic inflammation are not seen (J:117880)
• bone marrow displays enhanced production of osteoclasts in response to cytokine stimulation, similar to mice homozygous for the Sh3bp2 allele alone

hematopoietic system
• bone marrow displays enhanced production of osteoclasts in response to cytokine stimulation, similar to mice homozygous for the Sh3bp2 allele alone

cellular
• bone marrow displays enhanced production of osteoclasts in response to cytokine stimulation, similar to mice homozygous for the Sh3bp2 allele alone

Mouse Models of Human Disease
OMIM IDRef(s)
NOT Cherubism 118400 J:117880


Mouse Genome Informatics
cx12
    Tnftm1Gkl/Tnftm1Gkl
Tnfrsf1atm1Gkl/Tnfrsf1atm1Gkl

involves: 129S/SvEv * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
N
• no liver inflammation is seen unlike in Tnfrsf1atm1Gkl homozygotes (J:92470)


Mouse Genome Informatics
cx13
    Tnftm1Gkl/Tnftm1Gkl
Zfp36tm1Pjb/Zfp36tm1Pjb

involves: 129S/SvEv * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• mice do not show improvement of the endothelial dysfunction seen in single Zfp36 homozygotes, with aortas still less responsive to acetylcholine-induced relaxation

cellular
• mice show a partial reduction of the enhanced reactive oxygen and nitrogen species (RONS) formation under PDBu-stimulated conditions in whole blood that is seen in single Zfp36 homozygotes

muscle
• mice do not show improvement of the endothelial dysfunction seen in single Zfp36 homozygotes, with aortas still less responsive to acetylcholine-induced relaxation


Mouse Genome Informatics
cx14
    Tnftm1Gkl/Tnftm1Gkl
Tnfaip3tm1Ama/Tnfaip3tm1Ama

involves: 129S/SvEv * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging

growth/size/body

immune system
• bone marrow derived macrophages produce more IL-6 and nitric oxide in response to LPS treatment compared to Tnfaip1tm1Ama heterozygous Tnftm1Gkl homozygous macrophages
• the absolute number and percentage of myeloid cells is increased in multiple tissues