Mouse Genome Informatics
hm1
    Col4a3tm1Jhm/Col4a3tm1Jhm
involves: 129S1/Sv * 129X1/SvJ
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Kidney abnormalities in Col4a3tm1Jhm/Col4a3tm1Jhm mice

mortality/aging
• most homozygotes die 3 weeks after birth (J:37017)
• only ~5% of homozygotes survive beyond 4 months of age (J:37017)
• mice do not survive beyond 32 weeks (J:207595)

renal/urinary system
• relative levels of urinary protein are similar in mutant and wild-type mice until ~P40, then rise many-fold in mutant mice (J:37017)
• notably, homozygotes do NOT exhibit hematuria (J:37017)
• predominant protein detected in urine is albumin
• at P>65, mutant kidneys appear mottled and wrinkled
• however, at ~5 weeks, mutant kidneys are still externally normal with only minor histological alterations relative to wild-type
• at P40, a few glomeruli exhibit patches of thickened, closed capillary loops
• homozygotes exhibit late-onset, progressive glomerulonephritis, leading to renal failure
• homozygotes exhibit a basket-weave thickening and lamellation of the glomerular basal lamina (BL) (J:37017)
• several changes in the molecular composition of BL are observed; some occur as early as P15 (J:37017)
• decellularized glomerulus basement membrane with a rough and blebby surface (J:207595)
• basket-weave thickening of the glomerular basal lamina (J:37017)
• diffuse (J:207595)
• at P40, homozygotes display accumulation of interstitial cells and extracellular matrix
• at P40, a few glomeruli exhibit retricted segments of thickened Bowman's capsule (crescents) and/or patches of thickened, closed capillary loops (segmental glomerulosclerosis) (J:37017)
• both the number of glomeruli affected and the severity of glomerulosclerotic defects rise subsequently (J:37017)
• at P40, a few glomeruli exhibit retricted segments of thickened Bowman's capsule (crescents)
• at P>65, mutant kidneys appear small relative to wild-type
• at P40, homozygotes display atrophic kidney tubules
• tubular protein cast
• homozygotes display impaired glomerular filtration leading to uremia
• late-onset, progressive glomerulonephritis leading to renal failure
• at P60, homozygotes display increased urinary volume relative to wild-type

homeostasis/metabolism
• in homozygotes, blood creatinine levels rise after P60
• in contrast, creatinine concentrations in urine decline after P60
• a small % of mutants maintain normal levels of blood creatinine and show a mild renal phenotype
• in homozygotes, blood urea nitrogen levels rise after P60, indicating compromised glomerular filtration
• in contrast, urea nitrogen concentrations in urine decline after P60, suggesting a tubular dysfunction
• notably, a small % of homozygotes maintain normal levels of blood urea as late as P100, and exhibit only a mild renal pathology
• relative levels of urinary protein are similar in mutant and wild-type mice until ~P40, then rise many-fold in mutant mice (J:37017)
• notably, homozygotes do NOT exhibit hematuria (J:37017)
• predominant protein detected in urine is albumin

behavior/neurological
• at 2-3 months, most homozygotes become lethargic

growth/size/body
• at 2-3 months, most homozygotes begin to loose weight

hearing/vestibular/ear
• variable penetrance; 3 out of 12 pairs of mutants analyzed showed significantly increased auditory thresholds relative to wild-type
• other mutants showed hearing within normal ranges of thresholds and sensitivities, suggesting that the hearing loss may be due to genetic background differences

immune system
• homozygotes exhibit late-onset, progressive glomerulonephritis, leading to renal failure

cardiovascular system
• at P40, a few glomeruli exhibit patches of thickened, closed capillary loops

Mouse Models of Human Disease
OMIM IDRef(s)
Alport Syndrome, Autosomal Recessive 203780 J:37017 , J:207595


Mouse Genome Informatics
cx2
    Col4a3tm1Jhm/Col4a3tm1Jhm
Mmp9tm1Tvu/Mmp9tm1Tvu

involves: 129S1/Sv * 129S6/SvEvTac * 129X1/SvJ
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
immune system
• double homozygotes exhibit no differences in the progression of glomerulonephritis compared with single Col4a3tm1Jhm mutants, suggesting that MMP9 does not play a major role in the progression of Alport syndrome

renal/urinary system
• double homozygotes exhibit no differences in the progression of glomerulonephritis compared with single Col4a3tm1Jhm mutants, suggesting that MMP9 does not play a major role in the progression of Alport syndrome
• at 8 weeks, double homozygotes exhibit the characteristic splitting and thickening of the glomerular basement membrane observed in the Col4a3tm1Jhm mouse model of Alport syndrome
• thickening of the glomerular basement membrane observed at 8 weeks

Mouse Models of Human Disease
OMIM IDRef(s)
Alport Syndrome, Autosomal Recessive 203780 J:63137


Mouse Genome Informatics
cx3
    Col4a3tm1Jhm/Col4a3tm1Jhm
Tg(Nphs1-rtTA*3G)8Jhm/0
Tg(tetO-COL4A3/Col4a3)#aJhm/0

involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * CBA
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
N
• doxycycline-treated mice survive beyond 32 weeks unlike Col4a3tm1Jhm homozygotes (J:207595)

renal/urinary system
N
• doxycycline-treated mice remain nonalbuminuric for months unlike Col4a3tm1Jhm homozygotes (J:207595)
• doxycycline-treated mice do not exhibit glomerulosclerosis or tubular protein cast unlike Col4a3tm1Jhm homozygotes (J:207595)
• some doxycycline-treated mice do not maintain podocyte foot process architecture
• however, many doxycycline-treated mice maintain podocyte foot process architecture unlike in Col4a3tm1Jhm homozygotes
• doxycycline-treated mice exhibit some blebs on the glomerulus basement membrane
• doxycycline-treated mice exhibit some of segmental glomerulus basement membrane thickening observed in Col4a3tm1Jhm homozygotes


Mouse Genome Informatics
cx4
    Col4a3tm1Jhm/Col4a3tm1Jhm
Gt(ROSA)26Sortm1(rtTA,EGFP)Nagy/Gt(ROSA)26Sor+
Tg(tetO-COL4A3/Col4a3)#aJhm/0

involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * CBA
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
renal/urinary system
N
• doxycycline-treated mice exhibit normal kidney architecture (J:207595)
• doxycycline-treated mice exhibit some of segmental glomerulus basement membrane thickening observed in Col4a3tm1Jhm homozygotes