Mouse Genome Informatics
hm
    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