Phenotypes associated with this allele

• Allele Symbol: Cfh^tm1Mbo
• Allele Name: targeted mutation 1, Marina Botto
• Allele ID: MGI:2384179
• Summary: 9 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Cfh^tm1Mbo/Cfh^tm1Mbo	B6.129-Cfh^tm1Mbo	MGI:5546609
hm2	Cfh^tm1Mbo/Cfh^tm1Mbo	involves: 129	MGI:3778088
hm3	Cfh^tm1Mbo/Cfh^tm1Mbo	involves: 129/Sv * C57BL/6	MGI:2662550
ht4	Cfh^tm1Mbo/Cfh^+	involves: 129/Sv * C57BL/6	MGI:3845064
cx5	Cfb^tm1Hrc/Cfb^+ Cfh^tm1Mbo/Cfh^tm1Mbo	involves: 129S/Sv * C57BL/6	MGI:3845066
cx6	Cfb^tm1Hrc/Cfb^tm1Hrc Cfh^tm1Mbo/Cfh^tm1Mbo	involves: 129S/Sv * C57BL/6	MGI:2662552
cx7	Cfh^tm1Mbo/Cfh^tm1Mbo Cfi^tm1Mcp/Cfi^tm1Mcp	involves: 129/Sv * C57BL/6	MGI:3778086
cx8	Cfh^tm1Mbo/Cfh^+ Cfi^tm1Mcp/Cfi^tm1Mcp	involves: 129/Sv * C57BL/6	MGI:3778085
cx9	Cfh^tm1Mbo/Cfh^tm1Mbo Tg(CAG-Cfh*)#Mcp/0	involves: 129/Sv * C57BL/6 * CBA	MGI:5432033

Genotype
MGI:5546609

hm1

• Allelic Composition: Cfh^tm1Mbo/Cfh^tm1Mbo
• Genetic Background: B6.129-Cfh^tm1Mbo

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

vision/eye

abnormal retina morphology ( J:125991 , J:203471 )

• aged mutants exhibit an increase in subretinal/Bruch's membrane region autofluorescence (J:125991)

• increase in C3 deposition in the retina of aged mutants (J:125991)

• 12 month old mutants exhibit large clusters of hyperfluorescent foci in the subretinal space and show an abundance of partially digested fluorescent deposits adjacent to the retinal pigment epithelium (J:203471)

• 12 month old mutants show C3 deposition in the retina and extensive deposition of amyloid beta on the basal side of retinal pigment epithelium (J:203471)

• 3 month old mutants treated in both prophylactic and therapeutic regimes with an anti-amyloid beta monoclonal antibody 6F6 show a reduction in accumulation of both amyloid beta and activated C3 deposition in the retina (J:203471)

abnormal retina rod bipolar cell morphology ( J:125991 )

• rod bipolar cells of aged mutants show more prominent and numerous fine dendrites sprouting into the outer nuclear layer than controls

abnormal retina layer morphology ( J:125991 )

• the interface between the retinal pigmented epithelium cell and the outer segment is abnormal with loss of the intimate relationship between the perpendicular outer segment tips and apical microvilli of the retinal pigmented epithelium

abnormal retina photoreceptor morphology ( J:125991 )

• short-wavelength cone opsin is redistributed from the outer segments to more proximal cell compartments in aged mutants

disorganized photoreceptor outer segment ( J:125991 )

• aged mutants show discrete regions of misaligned, disorganized photoreceptor outer segments

• many outer segments are bent and some lie horizontally along the apical aspect of the retinal pigmented epithelium

abnormal retina pigment epithelium morphology ( J:125991 )

• the distribution of organelles within the retinal pigment epithelial layer is different, with the organelles dispersed throughout the retinal pigment epithelial instead of concentrated toward the apical aspect of the cell as in controls

• older mutants exhibit a decrease in the amount of sub- retinal pigment epithelial electron-dense material

abnormal Bruch membrane morphology ( J:125991 )

• 29% decrease in Bruch's membrane thickness in aged mutants

decreased a-wave amplitude ( J:125991 )

• rod photoreceptor function is impaired in aged mutants as indicated by a reduction in amplitude and change in slope of the a-wave of the ERG

• however, minimal impairment of cone function is seen

decreased b-wave amplitude ( J:125991 )

• electroretinography shows a reduction b-wave amplitudes with increasing stimulus intensity in aged mutants

decreased visual acuity ( J:125991 )

• 2 year old mutants exhibit a greater reduction in visual acuity than controls

nervous system

amyloid beta deposits ( J:203471 )

• the basal side of retinal pigment epithelium shows extensive deposition of amyloid beta in 10 week and 12 month old mutants

• increase in the rate of amyloid beta deposition at 3, 6, and 12 months of age compared to controls

• 3 month old mutants treated in both prophylactic and therapeutic regimes with an anti-amyloid beta monoclonal antibody 6F6 show a reduction in accumulation of both amyloid beta and activated C3 deposition in the retina

abnormal retina rod bipolar cell morphology ( J:125991 )

• rod bipolar cells of aged mutants show more prominent and numerous fine dendrites sprouting into the outer nuclear layer than controls

abnormal retina photoreceptor morphology ( J:125991 )

• short-wavelength cone opsin is redistributed from the outer segments to more proximal cell compartments in aged mutants

disorganized photoreceptor outer segment ( J:125991 )

• aged mutants show discrete regions of misaligned, disorganized photoreceptor outer segments

• many outer segments are bent and some lie horizontally along the apical aspect of the retinal pigmented epithelium

pigmentation

abnormal retina pigment epithelium morphology ( J:125991 )

• the distribution of organelles within the retinal pigment epithelial layer is different, with the organelles dispersed throughout the retinal pigment epithelial instead of concentrated toward the apical aspect of the cell as in controls

• older mutants exhibit a decrease in the amount of sub- retinal pigment epithelial electron-dense material

homeostasis/metabolism

amyloid beta deposits ( J:203471 )

• the basal side of retinal pigment epithelium shows extensive deposition of amyloid beta in 10 week and 12 month old mutants

• increase in the rate of amyloid beta deposition at 3, 6, and 12 months of age compared to controls

• 3 month old mutants treated in both prophylactic and therapeutic regimes with an anti-amyloid beta monoclonal antibody 6F6 show a reduction in accumulation of both amyloid beta and activated C3 deposition in the retina

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
age related macular degeneration 4		DOID:0110017	OMIM:610698	J:203471

Genotype
MGI:3778088

hm2

• Allelic Composition: Cfh^tm1Mbo/Cfh^tm1Mbo
• Genetic Background: involves: 129

renal/urinary system

glomerulonephritis ( J:131403 )

• at 8 months, animals show membranoproliferative glomerulonephritis type II (MPGN2)

renal glomerular protein deposits ( J:131403 )

• C3 deposition along glomerulus basement membrane (GBM) is significantly increased relative to controls; pattern is linear capillary wall deposition compared to the mesangial distribution observed in Cfi-deficient mice

immune system

abnormal complement protein level ( J:125860 )

• spontaneous glomerular basement membrane C3 deposition

decreased circulating complement protein level ( J:125860 , J:131403 )

• decrease in C3 levels (J:125860)

• median plasma level of complement protein C3 is significantly lower than in wild-type or Cfi^tm1Mcp animals (J:131403)

glomerulonephritis ( J:131403 )

• at 8 months, animals show membranoproliferative glomerulonephritis type II (MPGN2)

homeostasis/metabolism

abnormal complement protein level ( J:125860 )

• spontaneous glomerular basement membrane C3 deposition

decreased circulating complement protein level ( J:125860 , J:131403 )

• decrease in C3 levels (J:125860)

• median plasma level of complement protein C3 is significantly lower than in wild-type or Cfi^tm1Mcp animals (J:131403)

Genotype
MGI:2662550

hm3

• Allelic Composition: Cfh^tm1Mbo/Cfh^tm1Mbo
• Genetic Background: involves: 129/Sv * C57BL/6

mortality/aging

premature death ( J:78193 )

• 6 of 26 (23%) of homozygotes die spontaneously by 8 months of age

renal/urinary system

abnormal kidney capillary morphology ( J:78193 )

• homozygotes that die spontaneously display peripheral capillary loop thickening with deposition of periodic acid-Schiff (PAS)-positive material

increased urine protein level ( J:78193 )

• moribund homozygotes display proteinuria

albuminuria ( J:78193 )

• homozygotes display significantly higher levels of albuminuria than wild-type control mice

• however, serum creatinine levels remain unaffected

hematuria ( J:78193 )

• moribund homozygotes display hematuria

abnormal renal glomerulus basement membrane morphology ( J:78193 )

• homozygotes that die spontaneously display a double-contour appearance of the glomerular basement membrane

abnormal renal glomerulus morphology ( J:78193 )

• homozygotes that die spontaneously display glomerulus hypercellularity, mesangial expansion, and thickening of the capillary walls with double contours

• EM indicates subendothelial electron-dense deposits, formation of new basement membrane on the endothelial side of the deposits, and mesangial cell interposition

increased mesangial cell number ( J:78193 )

• homozygotes that die spontaneously exhibit marked mesangial hypercellularity

mesangial cell interposition ( J:78193 )

• homozygotes that die spontaneously exhibit mesangial cell interposition

glomerulonephritis ( J:78193 )

• by 8 months of age, all homozygotes show histologic evidence of membranoproliferative glomerulonephritis (MPGN); however, renal hemolytic uremic syndrome is not observed and the peripheral blood film is normal

• in response to sheep nephrotoxic serum (NTS) administration, pre-immunized homozygotes show significantly higher mortality than wild-type mice (median survival is 4 vs 14 days, respectively), exhibit severe albuminuria, hemoglobinuria and hypoalbuminemia at 3 days, and develop severe renal disease within 5 days of NTS treatment

expanded mesangial matrix ( J:78193 )

• homozygotes that die spontaneously exhibit marked mesangial matrix expansion

renal glomerular protein deposits ( J:78193 )

• capillary wall and mesangial deposition of both C3 and C9 is observed, whereas IgG shows a predominantly mesangial distribution

renal glomerular immunoglobulin deposits ( J:78193 )

immune system

decreased circulating complement protein level ( J:78193 )

• homozygotes exhibit significantly reduced plasma levels of complement protein C3, which are mostly below the detection limit of the assay (30 mg/l)

• in homozygotes, most plasma C3 is in the form of C3b

increased susceptibility to type III hypersensitivity reaction ( J:78193 )

• homozygotes develop membranoproliferative glomerulonephritis (MPGN) due to uncontrolled C3 activation and are hypersensitive to developing renal injury caused by immune complexes

• at 4 days of age, homozygotes show marked capillary wall deposition of C3 and C9 in the glomeruli in the absence of detectable IgG

• at 2 months of age, linear subendothelial electron-dense deposits are noted in the capillary wall in addition to the deposits of C3 and C9 detected by immunofluorescence; however, renal function (as determined by serum albumin, creatinine and urine protein loss) is normal, and there is no localization of IgG in the deposits at this age

• by 8 months of age, all homozygotes display histological evidence of MPGN by light microscopy, whereas none of the heterozygous or wild-type mice show MPGN

glomerulonephritis ( J:78193 )

• by 8 months of age, all homozygotes show histologic evidence of membranoproliferative glomerulonephritis (MPGN); however, renal hemolytic uremic syndrome is not observed and the peripheral blood film is normal

• in response to sheep nephrotoxic serum (NTS) administration, pre-immunized homozygotes show significantly higher mortality than wild-type mice (median survival is 4 vs 14 days, respectively), exhibit severe albuminuria, hemoglobinuria and hypoalbuminemia at 3 days, and develop severe renal disease within 5 days of NTS treatment

homeostasis/metabolism

decreased circulating complement protein level ( J:78193 )

• homozygotes exhibit significantly reduced plasma levels of complement protein C3, which are mostly below the detection limit of the assay (30 mg/l)

• in homozygotes, most plasma C3 is in the form of C3b

increased urine protein level ( J:78193 )

• moribund homozygotes display proteinuria

albuminuria ( J:78193 )

• homozygotes display significantly higher levels of albuminuria than wild-type control mice

• however, serum creatinine levels remain unaffected

hematuria ( J:78193 )

• moribund homozygotes display hematuria

cardiovascular system

abnormal kidney capillary morphology ( J:78193 )

• homozygotes that die spontaneously display peripheral capillary loop thickening with deposition of periodic acid-Schiff (PAS)-positive material

cellular

increased mesangial cell number ( J:78193 )

• homozygotes that die spontaneously exhibit marked mesangial hypercellularity

mesangial cell interposition ( J:78193 )

• homozygotes that die spontaneously exhibit mesangial cell interposition

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
membranoproliferative glomerulonephritis		DOID:2920	OMIM:305800	J:78193

Genotype
MGI:3845064

ht4

• Allelic Composition: Cfh^tm1Mbo/Cfh⁺
• Genetic Background: involves: 129/Sv * C57BL/6

homeostasis/metabolism

decreased circulating complement protein level ( J:78193 )

• heterozygotes display significantly lower amounts of plasma C3 than wild-type mice, suggesting that the physiological control of spontaneous C3 activation is impaired

• however, heterozygotes are viable and show no histologic evidence of membranoproliferative glomerulonephritis (MPGN)

immune system

decreased circulating complement protein level ( J:78193 )

• heterozygotes display significantly lower amounts of plasma C3 than wild-type mice, suggesting that the physiological control of spontaneous C3 activation is impaired

• however, heterozygotes are viable and show no histologic evidence of membranoproliferative glomerulonephritis (MPGN)

Genotype
MGI:3845066

cx5

• Allelic Composition: Cfb^tm1Hrc/Cfb⁺; Cfh^tm1Mbo/Cfh^tm1Mbo
• Genetic Background: involves: 129S/Sv * C57BL/6

immune system

decreased circulating complement protein level ( J:78193 )

• at 2 months of age, mutant mice show undetectable plasma C3 levels

renal/urinary system

renal glomerular protein deposits ( J:78193 )

• at 2 months of age, mutant mice exhibit both capillary wall glomerular C3 deposition and subendothelial electron-dense deposits

homeostasis/metabolism

decreased circulating complement protein level ( J:78193 )

• at 2 months of age, mutant mice show undetectable plasma C3 levels

Genotype
MGI:2662552

cx6

• Allelic Composition: Cfb^tm1Hrc/Cfb^tm1Hrc; Cfh^tm1Mbo/Cfh^tm1Mbo
• Genetic Background: involves: 129S/Sv * C57BL/6

normal phenotype

no abnormal phenotype detected ( J:78193 )

• at 2 months of age, double homozygotes have normal amounts of plasma C3, with no evidence of capillary wall glomerular C3 deposition and subendothelial electron-dense deposits

• unlike Cfh^tm1Mbo mice, double homozygotes show normal kidney histology and function with no evidence of GBM abnormalities at 8 months of age

• also unlike Cfh^tm1Mbo mice which develop severe renal disease within 5 days of receiving sheep nephrotoxic serum (NTS), double homozygotes remain healthy at this stage

Genotype
MGI:3778086

cx7

• Allelic Composition: Cfh^tm1Mbo/Cfh^tm1Mbo; Cfi^tm1Mcp/Cfi^tm1Mcp
• Genetic Background: involves: 129/Sv * C57BL/6

renal/urinary system

renal/urinary system phenotype ( J:131403 )

N • no membranoproliferative glomerulonephritis type II (MPGN2) is observed at 8 months compared with Cfh-null animals

renal glomerular protein deposits ( J:131403 )

• C3 deposition along glomerulus basement membrane (GBM) is identical to that observed in Cfh-deficient kidneys (significantly increased relative to controls)

homeostasis/metabolism

abnormal circulating protein level ( J:131403 )

• median plasma level of complement protein C3 is significantly higher than Cfh^tm1Mbo-deficient animals and is similar to Cfi-null mice

• no cleavage of C3 is detected in plasma

Genotype
MGI:3778085

cx8

• Allelic Composition: Cfh^tm1Mbo/Cfh⁺; Cfi^tm1Mcp/Cfi^tm1Mcp
• Genetic Background: involves: 129/Sv * C57BL/6

renal/urinary system

renal glomerular protein deposits ( J:131403 )

• C3 deposition along glomerulus basement membrane (GBM) is identical to that observed in Cfi-deficient kidneys (significantly increased relative to controls)

Genotype
MGI:5432033

cx9

• Allelic Composition: Cfh^tm1Mbo/Cfh^tm1Mbo; Tg(CAG-Cfh*)#Mcp/0
• Genetic Background: involves: 129/Sv * C57BL/6 * CBA

mortality/aging

premature death ( J:125860 )

• all mice develop hematuria and anasarca or die before 12 weeks of age

renal/urinary system

hematuria ( J:125860 )

• all mice develop hematuria and anasarca or die before 12 weeks of age

• at 8 weeks of age most (9 of 15) mice develop hematuria and anasarca

kidney failure ( J:125860 )

• associated with renal thrombotic microangiopathy

hematopoietic system

schistocytosis ( J:125860 )

• red cell fragmentation in the peripheral blood in mice with hematuria

thrombocytopenia ( J:125860 )

• in mice with hematuria

homeostasis/metabolism

increased blood urea nitrogen level ( J:125860 )

• in mice with hematuria

abnormal kidney thrombosis ( J:125860 )

• thrombotic microangiopathy is seen in mice with hematuria

anasarca ( J:125860 )

• all mice develop hematuria and anasarca (generalized edema) or die before 12 weeks of age

• at 8 weeks of age most (9 of 15) mice develop hematuria and anasarca

abnormal complement protein level ( J:125860 )

• C3 deposition along the endothelium, within the smooth muscle of renal arteries and within the glomerular mesangium and capillary walls

abnormal circulating complement protein level ( J:125860 )

• decrease in C3 levels, but increased compared to mice homozygous for Cfh^tm1Mbo alone

hematuria ( J:125860 )

• all mice develop hematuria and anasarca or die before 12 weeks of age

• at 8 weeks of age most (9 of 15) mice develop hematuria and anasarca

immune system

abnormal complement protein level ( J:125860 )

• C3 deposition along the endothelium, within the smooth muscle of renal arteries and within the glomerular mesangium and capillary walls

abnormal circulating complement protein level ( J:125860 )

• decrease in C3 levels, but increased compared to mice homozygous for Cfh^tm1Mbo alone

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
hemolytic-uremic syndrome		DOID:12554		J:125860