Phenotypes associated with this allele

• Allele Symbol: Irak3^tm1Flv
• Allele Name: targeted mutation 1, Richard A Flavell
• Allele ID: MGI:2384197
• Summary: 2 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Irak3^tm1Flv/Irak3^tm1Flv	involves: 129S1/Sv * C57BL/6	MGI:3584247
hm2	Irak3^tm1Flv/Irak3^tm1Flv	NOD.129S1(B6)-Irak3^tm1Flv	MGI:5800315

Genotype
MGI:3584247

hm1

• Allelic Composition: Irak3^tm1Flv/Irak3^tm1Flv
• Genetic Background: involves: 129S1/Sv * C57BL/6

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

Small size and reduced total bone mineral density in Irak3^tm1Flv/Irak3^tm1Flv mice

immune system

abnormal immune system morphology ( J:78189 )

increased neutrophil cell number ( J:78189 )

• increased numbers of polymorphonuclear cells found in Peyer's patches

increased osteoclast cell number ( J:98035 )

• increased numbers of osteoclasts per unit area of bone surface

abnormal Peyer's patch morphology ( J:78189 )

• shows hemorrhaging

enlarged Peyer's patches ( J:78189 )

• grossly enlarged after infection with gram negative bacteria

increased interleukin-12b secretion ( J:78189 )

• increased amounts of Il12p40 produced by macrophage when challenged by either gram negative or gram positive bacteria

increased interleukin-6 secretion ( J:78189 )

• increased amounts produced by macrophage when challenged by either gram negative or gram positive bacteria

increased tumor necrosis factor secretion ( J:78189 )

• increased amounts produced by macrophage when challenged by gram negative bacteria

abnormal inflammatory response ( J:78189 )

increased susceptibility to endotoxin shock ( J:78189 )

• decreased tolerance to endotoxin

abnormal innate immunity ( J:78189 )

• enhanced innate immunity

• bacterial load not greatly increased in spleens of mice with bacterial infections

abnormal osteoclast physiology ( J:98035 )

• bone marrow macrophage have a reduced proliferation rate but fuse more rapidly

• osteoclasts are generated more rapidly and have more prolonged life spans

skeleton

increased osteoclast cell number ( J:98035 )

• increased numbers of osteoclasts per unit area of bone surface

abnormal osteoclast physiology ( J:98035 )

• bone marrow macrophage have a reduced proliferation rate but fuse more rapidly

• osteoclasts are generated more rapidly and have more prolonged life spans

decreased diameter of femur ( J:98035 )

• decreased diameter of the femur in both sexes

kyphosis ( J:98035 )

• develops by 4 months of age

abnormal compact bone morphology ( J:98035 )

• lower cortical bone content at 4 months of age in the femur

decreased compact bone thickness ( J:98035 )

• cortical thickness of the femur reduced in males

increased osteoblast cell number ( J:98035 )

• increased numbers of osteoblasts seen in males

abnormal trabecular bone morphology ( J:98035 )

• trabecular bone content at epiphyses reduced

decreased trabecular bone volume ( J:98035 )

• 60% reduction in trabecular bone volume

growth/size/body

decreased body size ( J:98035 )

• by 4 months of age

hematopoietic system

increased neutrophil cell number ( J:78189 )

• increased numbers of polymorphonuclear cells found in Peyer's patches

increased osteoclast cell number ( J:98035 )

• increased numbers of osteoclasts per unit area of bone surface

abnormal osteoclast physiology ( J:98035 )

• bone marrow macrophage have a reduced proliferation rate but fuse more rapidly

• osteoclasts are generated more rapidly and have more prolonged life spans

limbs/digits/tail

decreased diameter of femur ( J:98035 )

• decreased diameter of the femur in both sexes

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
osteoporosis		DOID:11476	OMIM:166710	J:98035

Genotype
MGI:5800315

hm2

• Allelic Composition: Irak3^tm1Flv/Irak3^tm1Flv
• Genetic Background: NOD.129S1(B6)-Irak3^tm1Flv

homeostasis/metabolism

impaired glucose tolerance ( J:229884 )

♀ • blood glucose levels of nondiabetic females at a prediabetic stage are higher at both 15 min and 30 min after glucose injection indicating impaired glucose tolerance

immune system

insulitis ( J:229884 )

♀ • although there are more islets with severe insulitis in wild-type mice, the total number of infiltrated islets is much higher in mutant females

abnormal T cell differentiation ( J:229884 )

♀ • in vitro, mutant dendritic cells promote more CD4+ and CD8+ T cells to differentiate into IFN-gamma and TNF-alpha producing Th1 and Tc2 cells, respectively

increased effector memory T-helper cell number ( J:229884 )

♀ • splenic T cells from 3 month old females show a higher proportion of effector/memory cells (CD44^hiCD62L^lo) compared with wild-type mice

abnormal T cell activation ( J:229884 )

♀ • females exhibit enhanced T-cell activation

♀ • splenic T cells from 3 month old females show a higher proportion of effector/memory cells (CD44^hiCD62L^lo) compared with wild-type mice

♀ • females exhibit more IFN-gamma-producing CD4+ T cells and more TNF-alpha-producing CD8+ T cells in splenocytes

♀ • the frequency of proinflammatory cytokine-producing CD4+ T cells is higher in the pancreatic lymph nodes of mutant mice compared with wild-type mice

♀ • however, the frequency of proinflammatory cytokine-producing CD8+ T cells from pancreatic lymph nodes and the number of regulatory T cells is similar to wild-type mice

abnormal professional antigen presenting cell physiology ( J:229884 )

♀ • antigen-presenting cells exhibit a more activated phenotype

♀ • higher number of CD11b+ macrophages and CD11c+ dendritic cells from 3 month old females express the activation/costimulatory marker CD80, CD86, and MHC class II molecules, and females show higher numbers of IFN-gamma-producing CD11b+ macrophages and CD11c+ dendritic cells, and a higher frequency of IL-6-producing and IL-12-producing CD11c+ cells, indicating that antigen-presenting cells are more activated and produce more type I T-helper cell-driven cytokines

abnormal dendritic cell physiology ( J:229884 )

♀ • a higher percentage of dendritic cells from mutant females express activation and costimulatory molecules compared to wild-type mice both without stimulation and in response to stimulation with different TLR agonists (LPS, CpG, or Pam3CKS4)

♀ • dendritic cells secrete higher levels of IL-1beta, IL-6, IL-12(p40) and IFN-gamma both in the absence of TLR ligation and following TLR ligation

♀ • in vitro, in the presence of anti-CD3 mAbs , mutant dendritic cells enhance the activation of both CD4+ and CD8+ T cells

increased susceptibility to autoimmune diabetes ( J:229884 )

♀ • females develop diabetes as early as 6-7 weeks of age, with a higher total incidence compared with onset at 11 and 14 week in heterozygotes and wild-type mice, respectively

♀ • males shows no difference in the development of diabetes compared to wild-type mice, although they show a trend toward early onset

♀ • adoptive transfer of mutant splenocytes into wild-type mice mice results in accelerated development of diabetes in recipient mice compared to transfer of wild-type splenocytes

increased anti-insulin autoantibody level ( J:229884 )

♀ • females show increased anti-insulin IgG autoantibody levels in the serum

endocrine/exocrine glands

insulitis ( J:229884 )

♀ • although there are more islets with severe insulitis in wild-type mice, the total number of infiltrated islets is much higher in mutant females

hematopoietic system

abnormal T cell differentiation ( J:229884 )

♀ • in vitro, mutant dendritic cells promote more CD4+ and CD8+ T cells to differentiate into IFN-gamma and TNF-alpha producing Th1 and Tc2 cells, respectively

increased effector memory T-helper cell number ( J:229884 )

♀ • splenic T cells from 3 month old females show a higher proportion of effector/memory cells (CD44^hiCD62L^lo) compared with wild-type mice

abnormal T cell activation ( J:229884 )

♀ • females exhibit enhanced T-cell activation

♀ • splenic T cells from 3 month old females show a higher proportion of effector/memory cells (CD44^hiCD62L^lo) compared with wild-type mice

♀ • females exhibit more IFN-gamma-producing CD4+ T cells and more TNF-alpha-producing CD8+ T cells in splenocytes

♀ • the frequency of proinflammatory cytokine-producing CD4+ T cells is higher in the pancreatic lymph nodes of mutant mice compared with wild-type mice

♀ • however, the frequency of proinflammatory cytokine-producing CD8+ T cells from pancreatic lymph nodes and the number of regulatory T cells is similar to wild-type mice

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
type 1 diabetes mellitus		DOID:9744	OMIM:222100	J:229884