Phenotypes associated with this allele

• Allele Symbol: Col4a3^tm1Dec
• Allele Name: targeted mutation 1, Dominic Cosgrove
• Allele ID: MGI:1857432
• Summary: 6 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Col4a3^tm1Dec/Col4a3^tm1Dec	129-Col4a3^tm1Dec/J	MGI:4452030
hm2	Col4a3^tm1Dec/Col4a3^tm1Dec	129X1/SvJ-Col4a3^tm1Dec	MGI:3510458
hm3	Col4a3^tm1Dec/Col4a3^tm1Dec	B6.129X1-Col4a3^tm1Dec	MGI:4868448
hm4	Col4a3^tm1Dec/Col4a3^tm1Dec	involves: 129X1/SvJ * C57BL/6	MGI:3510446
cx5	Col4a3^tm1Dec/Col4a3^tm1Dec Itga1^tm1Gdnr/Itga1^tm1Gdnr	involves: 129S4/SvJae * 129X1/SvJ * BALB/c	MGI:3583734
cx6	Col4a3^tm1Dec/Col4a3^tm1Dec Sostdc1^tm1Myan/Sostdc1^tm1Myan	involves: 129X1/SvJ	MGI:4452039

Genotype
MGI:4452030

hm1

• Allelic Composition: Col4a3^tm1Dec/Col4a3^tm1Dec
• Genetic Background: 129-Col4a3^tm1Dec/J

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

Sostdc1^tm1Myan/Sostdc1^tm1Myan Col4a3^tm1Dec/Col4a3^tm1Dec mice show less glomerular and tubular injury than Col4a3^tm1Dec/Col4a3^tm1Dec mice

mortality/aging

decreased survivor rate ( J:158731 )

• impaired survival compared to Col4a3^tm1Dec Sostdc1^tm1Myan double homozygotes beyond 13 weeks of age

premature death ( J:158731 )

• impaired survival compared to Col4a3^tm1Dec Sostdc1^tm1Myan double homozygotes beyond 13 weeks of age

renal/urinary system

glomerulus hemorrhage ( J:158731 )

• intraglomerular hemorrhage at 6 weeks of age

increased urine protein level ( J:158731 )

• at 5 weeks of age, proteinuria is initiated

albuminuria ( J:158731 )

abnormal renal glomerulus basement membrane morphology ( J:158731 )

• irregular thickening and splitting of the glomerular basement membrane at 4 weeks of age by electron microscopy

increased renal glomerulus basement membrane thickness ( J:158731 )

• irregular thickening at 4 weeks of age

abnormal renal glomerulus morphology ( J:158731 )

• at 6 weeks of age, minor glomerular lesions are occasionally observed by light microscopy

glomerulonephritis ( J:158731 )

• progressive glomerulonephritis

glomerulosclerosis ( J:158731 )

• 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

renal interstitial fibrosis ( J:158731 )

• at 10 weeks of age, severe glomerular lesions associated with tubulointerstitial fibrosis are observed

renal tubule atrophy ( J:158731 )

• at 10 weeks of age mice demonstrate tubular atrophy

renal cast ( J:158731 )

• renal cast formation at 10 weeks of age

kidney failure ( J:158731 )

• at 10 weeks of age renal function is deteriorating

homeostasis/metabolism

increased circulating creatinine level ( J:158731 )

• at 10 weeks of age

increased blood urea nitrogen level ( J:158731 )

• at 10 weeks of age

increased urine protein level ( J:158731 )

• at 5 weeks of age, proteinuria is initiated

albuminuria ( J:158731 )

immune system

glomerulonephritis ( J:158731 )

• progressive glomerulonephritis

cardiovascular system

glomerulus hemorrhage ( J:158731 )

• intraglomerular hemorrhage at 6 weeks of age

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
autosomal recessive Alport syndrome		DOID:0110033	OMIM:203780	J:158731

Genotype
MGI:3510458

hm2

• Allelic Composition: Col4a3^tm1Dec/Col4a3^tm1Dec
• Genetic Background: 129X1/SvJ-Col4a3^tm1Dec

hearing/vestibular/ear

abnormal cochlear basement membrane morphology ( J:91619 , J:98449 )

• 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)

abnormal stria vascularis morphology ( 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

abnormal stria vascularis vasculature morphology ( J:91619 )

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

increased or absent threshold for auditory brainstem response ( J:91619 )

• 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

sensorineural hearing loss ( J:91619 )

• homozygotes display a moderate, high frequency, progressive sensorineural hearing loss

cardiovascular system

abnormal stria vascularis vasculature morphology ( J:91619 )

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

cellular

abnormal cochlear basement membrane morphology ( J:91619 , J:98449 )

• 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		DO ID	OMIM ID(s)	Ref(s)
autosomal recessive Alport syndrome		DOID:0110033	OMIM:203780	J:91619

Genotype
MGI:4868448

hm3

• Allelic Composition: Col4a3^tm1Dec/Col4a3^tm1Dec
• Genetic Background: B6.129X1-Col4a3^tm1Dec

mortality/aging

premature death ( J:167404 )

• mice die between 23 and 30 weeks

renal/urinary system

increased urine protein level ( J:167404 )

• at 22 weeks

glomerulonephritis ( J:167404 )

• beginning at 12 weeks and extensive at 22 weeks

podocyte foot process effacement ( J:167404 )

• at 22 weeks

abnormal renal glomerulus basement membrane thickness ( J:167404 )

• at 22 weeks, the glomerular basement membrane exhibits focal thinning and thickening compared to in wild-type mice

renal interstitial fibrosis ( J:167404 )

• beginning at 12 weeks and extensive at 22 weeks

renal tubule atrophy ( J:167404 )

• beginning at 12 weeks and extensive at 22 weeks, mice exhibit tubular atrophy unlike wild-type mice

homeostasis/metabolism

increased circulating creatinine level ( J:167404 )

• at 22 weeks

increased urine protein level ( J:167404 )

• at 22 weeks

immune system

glomerulonephritis ( J:167404 )

• beginning at 12 weeks and extensive at 22 weeks

Genotype
MGI:3510446

hm4

• Allelic Composition: Col4a3^tm1Dec/Col4a3^tm1Dec
• Genetic Background: involves: 129X1/SvJ * C57BL/6

mortality/aging

premature death ( J:37963 )

• homozygotes die when end-stage renal disease develops at ~14 weeks of age

homeostasis/metabolism

increased blood urea nitrogen level ( J:37963 )

• blood urea nitrogen levels begin to rise at ~10 weeks, and show a 10-fold increase over wild-type levels at ~14 weeks

albuminuria ( J:37963 )

• homozygotes develop proteinuria at ~5 weeks

• the majority of protein is of a molecular size consistent with mouse serum albumin

hematuria ( J:37963 )

• as early as 2 weeks, homozygotes exhibit microhematuria which persists at relatively constant levels through the course of renal disease

immune system

glomerulonephritis ( J:37963 )

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

renal/urinary system

abnormal glomerular capillary morphology ( J:37963 )

• at 8 weeks, homozygotes display thickened capillary walls with a rounded appearance

• by 14 weeks, half of the glomeruli are fibrotic with collapsed capillaries

increased mesangial cell number ( J:37963 )

• at 4 weeks, mutants show a mild expansion of mesangial cells in most glomeruli

albuminuria ( J:37963 )

• homozygotes develop proteinuria at ~5 weeks

• the majority of protein is of a molecular size consistent with mouse serum albumin

hematuria ( J:37963 )

• as early as 2 weeks, homozygotes exhibit microhematuria which persists at relatively constant levels through the course of renal disease

glomerulonephritis ( J:37963 )

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

abnormal podocyte morphology ( J:37963 )

• at end-stage, localized obliteration of podocytes is quite common

podocyte foot process effacement ( J:37963 , J:91619 )

• 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)

podocyte microvillus transformation ( J:37963 )

• by 8 weeks of age, an abundance of epithelial cell microvilli are observed

abnormal renal glomerulus basement membrane thickness ( J:37963 )

• 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

expanded mesangial matrix ( J:37963 )

• 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

renal glomerulus fibrosis ( J:37963 )

• by 14 weeks, half of the glomeruli are fibrotic

small kidney ( J:37963 )

• by end-stage, the mutant kidney is 30-50% smaller by mass than that of wild-type mice

granular kidney ( J:37963 )

• at end-stage, the mutant kidney has a rough granular appearance

pale kidney ( J:37963 )

• at end-stage, the mutant kidney is pale

vision/eye

abnormal lens morphology ( J:37963 )

• 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

abnormal cochlear basement membrane morphology ( J:91619 )

• 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

abnormal membranous labyrinth morphology ( J:91619 )

• homozygotes exhibit absence of the COL4A3 and COL4A4 chains throughout the membranous labyrinth

abnormal stria vascularis morphology ( J:91619 )

• 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

abnormal stria vascularis vasculature morphology ( J:91619 )

• endothelial cells lining the strial vessels are swollen and contain numerous vacuoles, resulting in capillaries with reduced internal diameters

abnormal strial marginal cell morphology ( J:91619 )

• 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

abnormal glomerular capillary morphology ( J:37963 )

• at 8 weeks, homozygotes display thickened capillary walls with a rounded appearance

• by 14 weeks, half of the glomeruli are fibrotic with collapsed capillaries

abnormal stria vascularis vasculature morphology ( J:91619 )

• endothelial cells lining the strial vessels are swollen and contain numerous vacuoles, resulting in capillaries with reduced internal diameters

cellular

increased mesangial cell number ( J:37963 )

• at 4 weeks, mutants show a mild expansion of mesangial cells in most glomeruli

abnormal cochlear basement membrane morphology ( J:91619 )

• 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		DO ID	OMIM ID(s)	Ref(s)
autosomal recessive Alport syndrome		DOID:0110033	OMIM:203780	J:37963

Genotype
MGI:3583734

cx5

• Allelic Composition: Col4a3^tm1Dec/Col4a3^tm1Dec; Itga1^tm1Gdnr/Itga1^tm1Gdnr
• Genetic Background: involves: 129S4/SvJae * 129X1/SvJ * BALB/c

renal/urinary system

abnormal kidney morphology ( J:71378 )

• decreased accumulation of myofibroblasts in kidneys of 7 week old mice compared to mice only homozygous for the collagen deficiency

tubular nephritis ( J:71378 )

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

abnormal renal glomerulus basement membrane morphology ( J:91620 )

• attenuated damage to the glomerular basement membrane although damage still present

kidney failure ( J:91620 )

• 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

increased circulating total protein level ( J:91620 )

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

immune system

tubular nephritis ( J:71378 )

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

Genotype
MGI:4452039

cx6

• Allelic Composition: Col4a3^tm1Dec/Col4a3^tm1Dec; Sostdc1^tm1Myan/Sostdc1^tm1Myan
• Genetic Background: involves: 129X1/SvJ

Sostdc1^tm1Myan/Sostdc1^tm1Myan Col4a3^tm1Dec/Col4a3^tm1Dec mice show less glomerular and tubular injury than Col4a3^tm1Dec/Col4a3^tm1Dec mice

mortality/aging

extended life span ( J:158731 )

• improved survival relative to Col4a3^tm1Dec single homozygotes beyond 13 weeks of age

renal/urinary system

albuminuria ( J:158731 )

• at 6 weeks of age have less severe albuminuria than in Col4a3^tm1Dec single homozygotes

glomerulonephritis ( J:158731 )

• severity is less than in Col4a3^tm1Dec single homozygotes

glomerulosclerosis ( J:158731 )

• 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 Col4a3^tm1Dec single homozygotes

renal interstitial fibrosis ( J:158731 )

• at 10 weeks of age mice demonstrate interstitial fibrosis that is less severe than in Col4a3^tm1Dec single homozygotes

renal tubule atrophy ( J:158731 )

• at 10 weeks of age mice demonstrate tubular atrophy that is less than in Col4a3^tm1Dec single homozygotes

renal cast ( J:158731 )

• at 10 weeks of age mice demonstrate cast formation that is less severe than in Col4a3^tm1Dec single homozygotes

immune system

glomerulonephritis ( J:158731 )

• severity is less than in Col4a3^tm1Dec single homozygotes

homeostasis/metabolism

increased circulating creatinine level ( J:158731 )

• at 10 weeks of age creatinine level is lower than in Col4a3^tm1Dec single homozygotes

increased blood urea nitrogen level ( J:158731 )

• at 10 weeks of age BUN is lower than in Col4a3^tm1Dec single homozygotes

albuminuria ( J:158731 )

• at 6 weeks of age have less severe albuminuria than in Col4a3^tm1Dec single homozygotes

cardiovascular system

decreased systemic arterial systolic blood pressure ( J:158731 )

• compared to Col4a3^tm1Dec single homozygotes at 5 weeks of age