Mouse Genome Informatics
hm1
    Col4a3tm1Dec/Col4a3tm1Dec
129-Col4a3tm1Dec/J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Sostdc1tm1Myan/Sostdc1tm1Myan Col4a3tm1Dec/Col4a3tm1Dec mice show less glomerular and tubular injury than Col4a3tm1Dec/Col4a3tm1Dec mice

mortality/aging
• impaired survival compared to Col4a3tm1Dec Sostdc1tm1Myan double homozygotes beyond 13 weeks of age
• impaired survival compared to Col4a3tm1Dec Sostdc1tm1Myan double homozygotes beyond 13 weeks of age

renal/urinary system
• intraglomerular hemorrhage at 6 weeks of age
• at 5 weeks of age, proteinuria is initiated
• at 10 weeks of age, severe glomerular lesions associated with tubulointerstitial fibrosis are observed
• irregular thickening and splitting of the glomerular basement membrane at 4 weeks of age by electron microscopy
• irregular thickening at 4 weeks of age
• at 6 weeks of age, minor glomerular lesions are occasionally observed by light microscopy
• progressive glomerulonephritis
• segmental sclerosis at 6 weeks of age
• at 10 weeks of age mice demonstrate glomerulosclerosis associated with inflammatory cell infiltration, interstitial fibrosis, tubular atrophy, and cast formation
• at 10 weeks of age mice demonstrate tubular atrophy
• renal cast formation at 10 weeks of age
• at 10 weeks of age renal function is deteriorating

homeostasis/metabolism
• at 5 weeks of age, proteinuria is initiated
• at 10 weeks of age, severe glomerular lesions associated with tubulointerstitial fibrosis are observed

immune system
• progressive glomerulonephritis

cardiovascular system
• intraglomerular hemorrhage at 6 weeks of age

Mouse Models of Human Disease
OMIM IDRef(s)
Alport Syndrome, Autosomal Recessive 203780 J:158731


Mouse Genome Informatics
hm2
    Col4a3tm1Dec/Col4a3tm1Dec
129X1/SvJ-Col4a3tm1Dec
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
hearing/vestibular/ear
• as early as 6 weeks, homozygotes display significant thickening of the strial capillary basement membrane (SCBM) (J:91619)
• at 7-9 weeks of age (i.e. prior to end-stage renal disease), SCBM thickening is associated with significantly elevated matrix metalloproteinases (MMP) deposition (J:98449)
• treatment with an inhibitor of MMP-2, -9, -12, and -14 exacerbates SCBM thickening, directly implicating altered basement membrane metabolism in maintaining normal SCBM composition and thickness (J:98449)
• at 7-9 weeks of age (i.e. prior to end-stage renal disease), homozygotes show matrix metalloproteinase dysregulation in the stria vascularis
• as early as 6 weeks, homozygotes display significant thickening of the strial capillary basement membrane (SCBM)
• at 6-8 weeks of age, auditory-evoked brainstem response measurements suggest a small increase in auditory thresholds across all frequencies tested with successive measurements on individual mutant mice
• homozygotes display a moderate, high frequency, progressive sensorineural hearing loss

cardiovascular system
• as early as 6 weeks, homozygotes display significant thickening of the strial capillary basement membrane (SCBM)

cellular
• as early as 6 weeks, homozygotes display significant thickening of the strial capillary basement membrane (SCBM) (J:91619)
• at 7-9 weeks of age (i.e. prior to end-stage renal disease), SCBM thickening is associated with significantly elevated matrix metalloproteinases (MMP) deposition (J:98449)
• treatment with an inhibitor of MMP-2, -9, -12, and -14 exacerbates SCBM thickening, directly implicating altered basement membrane metabolism in maintaining normal SCBM composition and thickness (J:98449)

Mouse Models of Human Disease
OMIM IDRef(s)
Alport Syndrome, Autosomal Recessive 203780 J:91619


Mouse Genome Informatics
hm3
    Col4a3tm1Dec/Col4a3tm1Dec
B6.129X1-Col4a3tm1Dec
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mice die between 23 and 30 weeks

renal/urinary system
• beginning at 12 weeks and extensive at 22 weeks
• beginning at 12 weeks and extensive at 22 weeks
• at 22 weeks, the glomerular basement membrane exhibits focal thinning and thickening compared to in wild-type mice
• beginning at 12 weeks and extensive at 22 weeks, mice exhibit tubular atrophy unlike wild-type mice

homeostasis/metabolism
• beginning at 12 weeks and extensive at 22 weeks

immune system
• beginning at 12 weeks and extensive at 22 weeks


Mouse Genome Informatics
hm4
    Col4a3tm1Dec/Col4a3tm1Dec
involves: 129X1/SvJ * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• homozygotes die when end-stage renal disease develops at ~14 weeks of age

homeostasis/metabolism
• blood urea nitrogen levels begin to rise at ~10 weeks, and show a 10-fold increase over wild-type levels at ~14 weeks
• homozygotes develop proteinuria at ~5 weeks
• the majority of protein is of a molecular size consistent with mouse serum albumin
• as early as 2 weeks, homozygotes exhibit microhematuria which persists at relatively constant levels through the course of renal disease
• by 14 weeks, half of the glomeruli are fibrotic

immune system
• homozygotes develop progressive glomerulonephritis and die with end-stage renal disease at ~14 weeks

renal/urinary system
• at 8 weeks, homozygotes display thickened capillary walls with a rounded appearance
• by 14 weeks, half of the glomeruli are fibrotic with collapsed capillaries
• homozygotes develop proteinuria at ~5 weeks
• the majority of protein is of a molecular size consistent with mouse serum albumin
• as early as 2 weeks, homozygotes exhibit microhematuria which persists at relatively constant levels through the course of renal disease
• by 14 weeks, half of the glomeruli are fibrotic
• homozygotes develop progressive glomerulonephritis and die with end-stage renal disease at ~14 weeks
• at end-stage, localized obliteration of podocytes is quite common
• at end-stage, pedicels are effaced (J:37963)
• at 4 weeks, homozygotes exhibit focal swelling and obliteration of the foot processes of podocytes (J:91619)
• by 8 weeks of age, an abundance of epithelial cell microvilli are observed
• the mutant GBM displays focal multilaminated thickening and thinning, beginning in the external capillary loops at 4 weeks and extending throughout the GBM by 8 weeks
• at 4 weeks, mutants show a mild expansion of mesangial cells in most glomeruli
• at 4 weeks, mutants show a mild expansion of mesangial matrix in most glomeruli
• by end-stage, the mesangial matrix is grossly expanded and fibrotic
• by end-stage, the mutant kidney is 30-50% smaller by mass than that of wild-type mice
• at end-stage, the mutant kidney has a rough granular appearance
• at end-stage, the mutant kidney is pale

vision/eye
• in contrast to Alport patients, homozygotes do NOT display lenticonus; however, the interior layer of the basement membrane encasing the anterior lens is irregular instead of smooth

hearing/vestibular/ear
• COL4A5 chain is absent from all cochlear basement membranes except those in the vessels of the stria vascularis; in contrast, expression of COL4A1 and COL4A2 chains is unchanged
• homozygotes show significant thinning of the basement membrane running from the spiral limbus, down the inner sulcus, across the basilar membrane and up to the spiral prominence
• basement membranes that normally ensheathe the root cells are not detectable
• basement membranes surrounding the strial vessels are significantly thickened, with some degree of variation
• a greater abundance of COL4A1 and 4A2 chains and entactin is noted in strial basement membranes
• homozygotes exhibit absence of the COL4A3 and COL4A4 chains throughout the membranous labyrinth
• basement membranes surrounding the strial vessels are significantly thickened, with some degree of variation
• at 5 weeks, mutant strial basement membranes are 1.6-3.1 thicker than normal, indicating that ultrastructural changes occur prior to the onset of uremia at ~12 weeks
• a greater abundance of COL4A1 and 4A2 chains and entactin is noted in strial basement membranes
• endothelial cells lining the strial vessels are swollen and contain numerous vacuoles, resulting in capillaries with reduced internal diameters
• homozygotes show variable changes in strial marginal cells, associated with enlarged, more rounded nuclei
• at 12-14 weeks, ~50% of mice with advanced glomerulonephritis show a reduction or loss of marginal cell basolateral infoldings

cardiovascular system
• at 8 weeks, homozygotes display thickened capillary walls with a rounded appearance
• by 14 weeks, half of the glomeruli are fibrotic with collapsed capillaries
• endothelial cells lining the strial vessels are swollen and contain numerous vacuoles, resulting in capillaries with reduced internal diameters

cellular
• COL4A5 chain is absent from all cochlear basement membranes except those in the vessels of the stria vascularis; in contrast, expression of COL4A1 and COL4A2 chains is unchanged
• homozygotes show significant thinning of the basement membrane running from the spiral limbus, down the inner sulcus, across the basilar membrane and up to the spiral prominence
• basement membranes that normally ensheathe the root cells are not detectable
• basement membranes surrounding the strial vessels are significantly thickened, with some degree of variation
• a greater abundance of COL4A1 and 4A2 chains and entactin is noted in strial basement membranes

Mouse Models of Human Disease
OMIM IDRef(s)
Alport Syndrome, Autosomal Recessive 203780 J:37963


Mouse Genome Informatics
cx5
    Col4a3tm1Dec/Col4a3tm1Dec
Itga1tm1Gdnr/Itga1tm1Gdnr

involves: 129S4/SvJae * 129X1/SvJ * BALB/c
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
renal/urinary system
• decreased accumulation of myofibroblasts in kidneys of 7 week old mice compared to mice only homozygous for the collagen deficiency
• infiltration of the kidney tubular interstitium by macrophage is less in 4 week old mice than in mice only homozygous for the collagen deficiency
• attenuated damage to the glomerular basement membrane although damage still present
• slower rate of renal disease progression
• end stage renal failure delayed to 14.5 weeks rather than 8.5 weeks as in mice only homozygous for the collagen deficiency

homeostasis/metabolism
• onset of proteinuria is delayed relative to mice only homozygous for the collagen deficiency

immune system
• infiltration of the kidney tubular interstitium by macrophage is less in 4 week old mice than in mice only homozygous for the collagen deficiency


Mouse Genome Informatics
cx6
    Col4a3tm1Dec/Col4a3tm1Dec
Sostdc1tm1Myan/Sostdc1tm1Myan

involves: 129X1/SvJ
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Sostdc1tm1Myan/Sostdc1tm1Myan Col4a3tm1Dec/Col4a3tm1Dec mice show less glomerular and tubular injury than Col4a3tm1Dec/Col4a3tm1Dec mice

mortality/aging
• improved survival relative to Col4a3tm1Dec single homozygotes beyond 13 weeks of age

renal/urinary system
• at 6 weeks of age have less severe albuminuria than in Col4a3tm1Dec single homozygotes
• at 10 weeks of age mice demonstrate interstitial fibrosis that is less severe than in Col4a3tm1Dec single homozygotes
• severity is less than in Col4a3tm1Dec single homozygotes
• at 10 weeks of age mice demonstrate glomerulosclerosis associated with inflammatory cell infiltration, interstitial fibrosis, tubular atrophy, and cast formation severity is less than in Col4a3tm1Dec single homozygotes
• at 10 weeks of age mice demonstrate tubular atrophy that is less than in Col4a3tm1Dec single homozygotes
• at 10 weeks of age mice demonstrate cast formation that is less severe than in Col4a3tm1Dec single homozygotes

immune system
• severity is less than in Col4a3tm1Dec single homozygotes

homeostasis/metabolism
• at 10 weeks of age creatinine level is lower than in Col4a3tm1Dec single homozygotes
• at 10 weeks of age BUN is lower than in Col4a3tm1Dec single homozygotes
• at 6 weeks of age have less severe albuminuria than in Col4a3tm1Dec single homozygotes
• at 10 weeks of age mice demonstrate interstitial fibrosis that is less severe than in Col4a3tm1Dec single homozygotes

cardiovascular system
• compared to Col4a3tm1Dec single homozygotes at 5 weeks of age