Phenotypes associated with this allele

• Allele Symbol: C4b^tm1Crr
• Allele Name: targeted mutation 1, Michael C Carroll
• Allele ID: MGI:1889070
• Summary: 5 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	C4b^tm1Crr/C4b^tm1Crr	involves: 129S4/SvJae	MGI:5296003
hm2	C4b^tm1Crr/C4b^tm1Crr	involves: 129S4/SvJae * C57BL/6	MGI:2429659
hm3	C4b^tm1Crr/C4b^tm1Crr	involves: 129S4/SvJae * C57BL/6J	MGI:3663104
cx4	C4b^tm1Crr/C4b^tm1Crr Fas^lpr/Fas^lpr	involves: 129S4/SvJae * C57BL/6 * MRL	MGI:3800668
cx5	C3^tm1Crr/C3^tm1Crr C4b^tm1Crr/C4b^tm1Crr Fas^lpr/Fas^lpr	involves: 129S4/SvJae * C57BL/6 * MRL	MGI:3800670

Genotype
MGI:5296003

hm1

• Allelic Composition: C4b^tm1Crr/C4b^tm1Crr
• Genetic Background: involves: 129S4/SvJae

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

renal/urinary system

glomerulonephritis ( J:44715 )

• reduced neutrophil infiltration of glomerulus relative to controls when injected with 0.5 mg and with 1.0mg of anti-glomerular basement membrane antiserum

homeostasis/metabolism

abnormal blood coagulation ( J:44715 )

• thrombus formation only moderately reduced

immune system

glomerulonephritis ( J:44715 )

• reduced neutrophil infiltration of glomerulus relative to controls when injected with 0.5 mg and with 1.0mg of anti-glomerular basement membrane antiserum

decreased susceptibility to Coronaviridae infection ( J:286325 )

• mice show some protection from intranasal infection with the mouse-adapted SARS-CoV MA15 , showing less weight loss than in wild-type controls but more weight loss than in C3^tm1Crr homozygotes

Genotype
MGI:2429659

hm2

• Allelic Composition: C4b^tm1Crr/C4b^tm1Crr
• Genetic Background: involves: 129S4/SvJae * C57BL/6

mortality/aging

increased susceptibility to bacterial infection induced morbidity/mortality ( J:30152 )

• increased mortality from GBS infection compared to controls is limited to the first 3 days after challenge

• mice challenged with group B Streptococci (GBS) infection become bacteremic within 3 days and die or clear bacteria and survive; C4b-deficient mice challenged with GBS infection showed a decreased LD₅₀ dose compared to immunocompetent controls (LD₅₀ dose: control 6.3 x 10⁴ vs. 2.4 x 10³ in C4b-deficient mice)

increased susceptibility to induced morbidity/mortality ( J:44240 )

• caecal ligation and puncture (CLP) causes greater mortality in mutants than wild-type in the first 24 hours after CLP (100 vs 20% mortality)

immune system

immune system phenotype ( J:30152 , J:64282 )

N • serum from C4-deficient mice has similar antibody-mediated opsonophagocytic killing of GBS to control serum (J:30152)

N • secondary immune responses are similar in wild-type and mutant mice, so helper T cell function is normal (J:64282)

N • B cells from deficient mice show normal proliferative effects in response to surface IgM crosslinking (J:64282)

abnormal spleen germinal center morphology ( J:64282 )

decreased spleen germinal center number ( J:64282 )

• after immunization, wild-type mice develop germinal centers (GC) in ~half of splenic follicles while ~10% of splenic follicles in C3-deficient mice contain GCs

decreased spleen germinal center size ( J:64282 )

• diameter of GCs are less than that observed in wild-type

abnormal humoral immune response ( J:64282 )

• when immunized with a 10-fold higher amount of bacteriophage, mice show a weak IgG response but response is still 10-fold lower than wild-type

• in response to immunization with bacteriophage (phiX174), a T cell dependent antigen, C4b-deficient mice mount a weak Ig M response but fail to switch to IgG

liver inflammation ( J:30152 )

• mild hepatitis is observed in a small number (1/11) of mice surviving systemic challenge with GBS doses of 10² to 10⁵ CFU upon necropsy 15 days post-challenge; there are aggregates of mononuclear or polymorphonuclear leukocytes in hepatic sinusoids; wild-type animals that receive higher doses of GBS showed similar lesions

decreased susceptibility to bacterial infection ( J:30152 )

• when pregnant dams are immunized with immune rabbit serum, pups are protected against lethal challenge on day 2 of life because of transfer of maternal antibodies to the pups (15/16 pups survive, similar to controls)

increased susceptibility to bacterial infection induced morbidity/mortality ( J:30152 )

• increased mortality from GBS infection compared to controls is limited to the first 3 days after challenge

• mice challenged with group B Streptococci (GBS) infection become bacteremic within 3 days and die or clear bacteria and survive; C4b-deficient mice challenged with GBS infection showed a decreased LD₅₀ dose compared to immunocompetent controls (LD₅₀ dose: control 6.3 x 10⁴ vs. 2.4 x 10³ in C4b-deficient mice)

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:120567 )

N • response to renal ischemia reperfusion injury is the same as in wild-type mice

hematopoietic system

abnormal spleen germinal center morphology ( J:64282 )

decreased spleen germinal center number ( J:64282 )

• after immunization, wild-type mice develop germinal centers (GC) in ~half of splenic follicles while ~10% of splenic follicles in C3-deficient mice contain GCs

decreased spleen germinal center size ( J:64282 )

• diameter of GCs are less than that observed in wild-type

cardiovascular system

decreased vascular permeability ( J:78613 )

• upeon reperfusion of ischemic intestine (jejunum), permeability index (PI) of injured C4b-deficient mice is reduced compared to control treated wild-type (PI of 2.20 vs 3.26 in controls)

digestive/alimentary system

abnormal intestine morphology ( J:78613 )

• mice show less evidence of infarction compared to controls

liver/biliary system

liver inflammation ( J:30152 )

• mild hepatitis is observed in a small number (1/11) of mice surviving systemic challenge with GBS doses of 10² to 10⁵ CFU upon necropsy 15 days post-challenge; there are aggregates of mononuclear or polymorphonuclear leukocytes in hepatic sinusoids; wild-type animals that receive higher doses of GBS showed similar lesions

Genotype
MGI:3663104

hm3

• Allelic Composition: C4b^tm1Crr/C4b^tm1Crr
• Genetic Background: involves: 129S4/SvJae * C57BL/6J

immune system

increased spleen weight ( J:111811 )

♀ • at 10 months of age, spleens of C4b-deficient females are enlarged with an average weight of 368 mg compared to controls which are ~100mg; most females have spleens 2-fold larger by weight, and 1/3 have spleens 4 times the average control weight

increased neutrophil cell number ( J:111811 )

• numbers are increased 4-fold over controls

increased macrophage cell number ( J:111811 )

• numbers are increased 2-fold over controls

increased spleen germinal center number ( J:111811 )

• spontaneous germinal center formation is observed in C4b-deficient mice

abnormal immune system physiology ( J:111811 )

• clearance of soluble immune complexes (IC) injected into mice is delayed initially in C4b-deficient mice, resulting in a 2- to 3-fold increase in circulating IC levels compared to C2-deficient or B6.129-Igh^b controls

• levels remain high for at least 70 minutes

increased anti-nuclear antigen antibody level ( J:111811 )

♀ • by 5-6 months of age, >50% of C4b-deficient females (on Igh^b haplotype homozygous background) have antinuclear antibody (ANA) levels comparable to Fas-deficient mice

♀ • males have ANA levels higher (but not significant) than controls

♀ • in 10-month old females, ANA levels as high as 1:30000 are present

increased anti-double stranded DNA antibody level ( J:111811 )

♀ • IgG autoantibody titers against dsDNA are increased over controls in females at 10 months of age

increased anti-single stranded DNA antibody level ( J:111811 )

♀ • IgG autoantibody titers against ss-DNA are increased over controls in females at 10 months of age

glomerulonephritis ( J:111811 )

♀ • ~50% of 10-month old female C4b-deficient mice show glomerulonephritis but no male do

renal/urinary system

abnormal renal glomerulus morphology ( J:111811 )

♀ • marked enlargement with hypercellularity is observed in the glomeruli of females at 10 months

glomerulonephritis ( J:111811 )

♀ • ~50% of 10-month old female C4b-deficient mice show glomerulonephritis but no male do

renal glomerular protein deposits ( J:111811 )

♀ • many female mice display mesangial deposition of immune complexes (ICs) of IgG and C3

hematopoietic system

increased spleen weight ( J:111811 )

♀ • at 10 months of age, spleens of C4b-deficient females are enlarged with an average weight of 368 mg compared to controls which are ~100mg; most females have spleens 2-fold larger by weight, and 1/3 have spleens 4 times the average control weight

increased neutrophil cell number ( J:111811 )

• numbers are increased 4-fold over controls

increased macrophage cell number ( J:111811 )

• numbers are increased 2-fold over controls

increased spleen germinal center number ( J:111811 )

• spontaneous germinal center formation is observed in C4b-deficient mice

growth/size/body

increased spleen weight ( J:111811 )

♀ • at 10 months of age, spleens of C4b-deficient females are enlarged with an average weight of 368 mg compared to controls which are ~100mg; most females have spleens 2-fold larger by weight, and 1/3 have spleens 4 times the average control weight

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
systemic lupus erythematosus		DOID:9074	OMIM:152700 OMIM:300809 OMIM:605480 OMIM:608437 OMIM:609903 OMIM:609939 OMIM:610065 OMIM:610066 OMIM:612254 OMIM:612378 OMIM:613145 OMIM:614420	J:111811

Genotype
MGI:3800668

cx4

• Allelic Composition: C4b^tm1Crr/C4b^tm1Crr; Fas^lpr/Fas^lpr
• Genetic Background: involves: 129S4/SvJae * C57BL/6 * MRL

immune system

enlarged spleen ( J:127292 )

• spleen mass is significantly increased relative to C3 /Fas^lpr or single Fas^lpr mutants at 17 weeks of age

enlarged cervical lymph nodes ( J:127292 )

• lymph node mass is increased relative to C3-null, Fas^lpr or single Fas^lpr mutants at 13 and 17 weeks of age

abnormal immune system physiology ( J:127292 )

• frequency of antibody-secreting cells (ASCs) or antibody-forming cells (AFCs) is significantly increased in spleen and bone marrow compared to C3-deficient Fas mutants

increased anti-nuclear antigen antibody level ( J:127292 )

• titers of serum ANA are significantly increased at 10, 13, and 17 weeks

increased anti-double stranded DNA antibody level ( J:127292 )

• anti-dsDNA titers are elevated significantly at 17 weeks

hematopoietic system

enlarged spleen ( J:127292 )

• spleen mass is significantly increased relative to C3 /Fas^lpr or single Fas^lpr mutants at 17 weeks of age

renal/urinary system

abnormal kidney morphology ( J:127292 )

• increased IgG deposition relative to C3/Fas mutants is observed in kidney sections

abnormal renal glomerulus morphology ( J:127292 )

• more severe glomerular abnormalities are observed relative to C3/Fas mutants

growth/size/body

enlarged spleen ( J:127292 )

• spleen mass is significantly increased relative to C3 /Fas^lpr or single Fas^lpr mutants at 17 weeks of age

Genotype
MGI:3800670

cx5

• Allelic Composition: C3^tm1Crr/C3^tm1Crr; C4b^tm1Crr/C4b^tm1Crr; Fas^lpr/Fas^lpr
• Genetic Background: involves: 129S4/SvJae * C57BL/6 * MRL

immune system

enlarged spleen ( J:127292 )

• spleen mass is significantly increased relative to C3-null, Fas^lpr or single Fas^lpr mutants at 17 weeks of age

enlarged cervical lymph nodes ( J:127292 )

• lymph node mass is increased relative to C3-null, Fas^lpr or single Fas^lpr mutants at 10 and 13 weeks of age

abnormal immune system physiology ( J:127292 )

• frequency of antibody-secreting cells (ASCs) or antibody-forming cells (AFCs) is significantly increased in spleen, bone marrow, and lymph nodes compared to C3-deficient Fas mutants or single Fas^lpr mutants

increased anti-nuclear antigen antibody level ( J:127292 )

• titers of serum ANA are significantly increased at 10 and 17 weeks, compared to single-deficient mice

increased anti-double stranded DNA antibody level ( J:127292 )

• anti-dsDNA titers are elevated significantly relative to C4, Fas double mutants

hematopoietic system

enlarged spleen ( J:127292 )

• spleen mass is significantly increased relative to C3-null, Fas^lpr or single Fas^lpr mutants at 17 weeks of age

renal/urinary system

abnormal kidney morphology ( J:127292 )

• increased IgG deposition relative to C3/Fas mutants is observed in kidney sections; deposition is similar to C4/Fas mutants

abnormal renal glomerulus morphology ( J:127292 )

• more severe glomerular abnormalities are observed relative to C3/Fas mutants, and pathology is similar to that of C4/Fas double mutants

growth/size/body

enlarged spleen ( J:127292 )

• spleen mass is significantly increased relative to C3-null, Fas^lpr or single Fas^lpr mutants at 17 weeks of age