Phenotypes Associated with This Genotype

Genotype
MGI:2176903

• Allelic Composition: Col4a3^tm1Jhm/Col4a3^tm1Jhm
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ

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

Kidney abnormalities in Col4a3^tm1Jhm/Col4a3^tm1Jhm mice

mortality/aging

premature death ( J:37017 , J:207595 )

• 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

increased urine protein level ( J:37017 , J:207595 )

• 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)

albuminuria ( J:37017 )

• predominant protein detected in urine is albumin

abnormal kidney morphology ( J:37017 )

• 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

abnormal glomerular capillary morphology ( J:37017 )

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

glomerulonephritis ( J:37017 )

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

abnormal podocyte foot process morphology ( J:207595 )

abnormal renal glomerulus basement membrane morphology ( J:37017 , J:207595 )

• 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)

increased renal glomerulus basement membrane thickness ( J:37017 , J:207595 )

• basket-weave thickening of the glomerular basal lamina (J:37017)

• diffuse (J:207595)

expanded mesangial matrix ( J:37017 )

• at P40, homozygotes display accumulation of interstitial cells and extracellular matrix

glomerulosclerosis ( J:37017 , J:207595 )

• 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)

glomerular crescent ( J:37017 )

• at P40, a few glomeruli exhibit retricted segments of thickened Bowman's capsule (crescents)

small kidney ( J:37017 )

• at P>65, mutant kidneys appear small relative to wild-type

renal tubule atrophy ( J:37017 )

• at P40, homozygotes display atrophic kidney tubules

renal cast ( J:207595 )

• tubular protein cast

decreased renal glomerular filtration rate ( J:37017 )

• homozygotes display impaired glomerular filtration leading to uremia

kidney failure ( J:37017 )

• late-onset, progressive glomerulonephritis leading to renal failure

polyuria ( J:37017 )

• at P60, homozygotes display increased urinary volume relative to wild-type

homeostasis/metabolism

uremia ( J:37017 )

increased circulating creatinine level ( J:37017 )

• 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

increased blood urea nitrogen level ( J:37017 )

• 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

increased urine protein level ( J:37017 , J:207595 )

• 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)

albuminuria ( J:37017 )

• predominant protein detected in urine is albumin

behavior/neurological

lethargy ( J:37017 )

• at 2-3 months, most homozygotes become lethargic

growth/size/body

decreased body weight ( J:37017 )

• at 2-3 months, most homozygotes begin to loose weight

hearing/vestibular/ear

increased or absent threshold for auditory brainstem response ( J:37017 )

• 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

glomerulonephritis ( J:37017 )

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

cardiovascular system

abnormal glomerular capillary morphology ( J:37017 )

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

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
autosomal recessive Alport syndrome		DOID:0110033	OMIM:203780	J:37017 , J:207595