Phenotypes associated with this allele

• Allele Symbol: Nr3c2^tm1Gsc
• Allele Name: targeted mutation 1, Gunther Schutz
• Allele ID: MGI:2441654
• Summary: 2 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Nr3c2^tm1Gsc/Nr3c2^tm1Gsc	involves: 129P2/OlaHsd * C57BL/6	MGI:3041700
ht2	Nr3c2^tm1Gsc/Nr3c2^+	involves: 129P2/OlaHsd * C57BL/6	MGI:3041780

Genotype
MGI:3041700

hm1

• Allelic Composition: Nr3c2^tm1Gsc/Nr3c2^tm1Gsc
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6

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

Histological and immunocytochemical kidney analysis of Nr3c2^tm1Gsc/Nr3c2^tm1Gsc mice

mortality/aging

postnatal lethality, complete penetrance ( J:77285 )

• all homozygotes died between postnatal days P8 and P13, on average at P10

• daily injection of betamethasone (a synthetic glucocorticoid), from P5 extended survival to ~17 days; however, betamethasone-treated homozygotes failed to thrive and eventually died

growth/size/body

weight loss ( J:77285 )

• homozygotes displayed weight loss prior to death; however, reduced weight gain was not attributed to growth inhibition

hematopoietic system

increased hematocrit ( J:77285 )

• at P8, the hematocrit was increased from 32% in wild-type to 44%, indicating severe dehydration

homeostasis/metabolism

increased circulating angiotensin II level ( J:77285 )

• plasma angiotensin II levels were increased 50-fold at P8

increased circulating aldosterone level ( J:77285 )

• plasma aldosterone levels were increased 65-fold at P8

increased circulating renin level ( J:77285 )

• plasma renin concentration was normal at P0 but increased 8-fold at P4

• plasma renin levels were increased 440-fold at P8

dehydration ( J:77285 )

• at P8, homozygotes were severely dehydrated

abnormal ion homeostasis ( J:77285 )

• amiloride-sensitive epithelial Na⁺ channel (ENaC)-mediated Na⁺ reabsorption was reduced to 24% in the kidney and to 16% in the colon

increased circulating potassium level ( J:77285 )

• homozygotes displayed hyperkalemia at P8

decreased circulating sodium level ( J:77285 )

• homozygotes displayed hyponatremia at P8

abnormal renal sodium reabsorption ( J:77285 )

• at P8, homozygotes displayed impaired distal tubular Na⁺ reabsorption relative to wild-type controls

• homozygotes displayed impaired amiloride-sensitive Na⁺ reabsorption, leading to changes similar to pseudohypoaldosteronism type 1

• amiloride-sensitive epithelial Na⁺ channel (ENaC)-mediated Na⁺ reabsorption was reduced to 24% in the kidney

increased urine sodium level ( J:77285 )

• at P8, homozygotes showed a significant increase in urine Na⁺ (35.4 +/- 3.3 mmol/l) relative to wild-type controls (9.1 +/- 1.2 mmol/l)

increased renin activity ( J:77285 )

• at P8, homozygotes exhibited a strong activation of the renin-angiotensin-aldosterone system, with a 440-fold increase in plasma renin levels, a 50-fold increase in plasma angiotensin II levels, and a 65-fold increase in plasma aldosterone levels relative to wild-type controls

• renin activity in the vascular pole region and along the entire afferent arteriole was highly increased along with the rise in plasma renin levels

renal/urinary system

renal/urinary system phenotype ( J:77285 )

N • homozygotes displayed a normal glomerular filtration rate relative to wild-type controls

increased urine sodium level ( J:77285 )

• at P8, homozygotes showed a significant increase in urine Na⁺ (35.4 +/- 3.3 mmol/l) relative to wild-type controls (9.1 +/- 1.2 mmol/l)

abnormal juxtaglomerular apparatus morphology ( J:77285 )

• at P8, the macula densa segment of the distal tubule appeared enlarged

• at P8, the extraglomerular mesangium showed significant hyperplasia

• at P8, renin-producing granular cells extended upstream along the afferent arteriole

• at P8, renin granules were detected in nearly all extraglomerular mesangium cells

• signs of changes at the glomerular vascular pole were first observed at P4

abnormal extraglomerular mesangial cell morphology ( J:77285 )

• at P8, the extraglomerular mesangium showed significant hyperplasia

• at P8, renin granules were detected in nearly all extraglomerular mesangium cells

abnormal juxtaglomerular cell morphology ( J:77285 )

• at P8, renin-producing granular cells extended upstream along the afferent arteriole

abnormal macula densa morphology ( J:77285 )

• at P8, the macula densa segment of the distal tubule appeared enlarged

abnormal renal glomerulus morphology ( J:77285 )

• at P8, homozygotes displayed morphological changes at the glomerular vascular pole

abnormal renal sodium ion transport ( J:77285 )

• homozygotes showed an 8-fold increase in fractional excretion of Na⁺ leading to hypovolemia

• however, after amiloride injection, homozygotes displayed a lower increase in the fractional excretion of Na⁺ (from 2.7 to 4.5%) than wild-type (0.3 to 8%) and heterozygous (0.9 to 8.5%) controls

abnormal renal sodium reabsorption ( J:77285 )

• at P8, homozygotes displayed impaired distal tubular Na⁺ reabsorption relative to wild-type controls

• homozygotes displayed impaired amiloride-sensitive Na⁺ reabsorption, leading to changes similar to pseudohypoaldosteronism type 1

• amiloride-sensitive epithelial Na⁺ channel (ENaC)-mediated Na⁺ reabsorption was reduced to 24% in the kidney

cardiovascular system

hypovolemia ( J:77285 )

• homozygotes showed an 8-fold increase in fractional excretion of Na⁺ leading to hypovolemia

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
autosomal dominant pseudohypoaldosteronism type 1		DOID:0060855	OMIM:177735	J:77285

Genotype
MGI:3041780

ht2

• Allelic Composition: Nr3c2^tm1Gsc/Nr3c2⁺
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6

homeostasis/metabolism

increased circulating angiotensin II level ( J:77285 )

• at P8, heterozygotes showed a ~3-fold increase in plasma angiotensin II levels relative to wild-type controls

increased circulating aldosterone level ( J:77285 )

• at P8, heterozygotes showed a 3-fold increase in plasma aldosterone levels relative to wild-type controls

increased circulating renin level ( J:77285 )

• at P8, heterozygotes showed a 3.5-fold increase in plasma renin concentration relative to wild-type controls

increased urine sodium level ( J:77285 )

• at P8, heterozygotes showed a significant increase in urine Na⁺ (19.6 +/- 2.5 mmol/l) relative to wild-type controls (9.1 +/- 1.2 mmol/l)

increased renin activity ( J:77285 )

• at P8, heterozygotes exhibited a moderate activation of the renin-angiotensin-aldosterone system with a ~3-fold increase in plasma renin, aldosterone and angiotensin II levels relative to wild-type controls

renal/urinary system

increased urine sodium level ( J:77285 )

• at P8, heterozygotes showed a significant increase in urine Na⁺ (19.6 +/- 2.5 mmol/l) relative to wild-type controls (9.1 +/- 1.2 mmol/l)

abnormal renal sodium ion transport ( J:77285 )

• at P8, heterozygotes showed a 3-fold increase in fractional excretion of Na⁺ relative to wild-type controls

• however, after amiloride injection, heterozygotes displayed a lower increase in the fractional excretion of Na⁺ (from 0.9 to 8.5%) than wild-type controls (0.3 to 8%)