Phenotypes Associated with This Genotype

Genotype
MGI:3619919

• Allelic Composition: Npr1^tm1Mae/Npr1^tm1Mae
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6

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

Cardiac hypertrophy in Npr1^tm1Mae/Npr1^tm1Mae male mice

mortality/aging

premature death ( J:74420 , J:101857 )

• at weaning, homozygotes are represented in normal Mendelian ratios; however, all (15 of 15) male but only 1 of 16 female homozygotes exhibit sudden death before 6 months of age (J:74420)

• notably, 7 of 7 male homozygotes die between 7 and 8 weeks when housed with littermates; when housed alone, all male homozygotes die beginning at ~9 weeks (J:74420)

• sudden death may be precipitated by stress (e.g. after prolonged voluntary exercise, placement with other males, or high-salt intake) (J:74420)

• Background Sensitivity: sudden death occuring in F2 generation males is no longer present in homozygotes after 6 or 7 backcrosses to C57BL/6, possibly due to genetic drifts and loss of modifying loci (J:101857)

cellular

myocardium necrosis ( J:74420 )

• at 3-5 months, some male homozygotes exhibit patchy areas of incipient myocyte death in the ventricles

cardiac interstitial fibrosis ( J:74420 )

• at 3-5 months, all (4 of 4) male homozygotes display perivascular fibrosis with variable scarring

• in contrast, only 1 of 5 female homozygotes display fibrotic foci at 6 months

cardiovascular system

aortic dissection ( J:74420 )

• at necropsy, 3 of 8 male homozygotes display aortic dissections

abnormal myocardium layer morphology ( J:74420 )

• at 3 to 5 months, male homozygotes with a hypertrophic myocardium show a >200% increase in myocyte cross-sectional area relative to wild-type mice

myocardium necrosis ( J:74420 )

• at 3-5 months, some male homozygotes exhibit patchy areas of incipient myocyte death in the ventricles

cardiac hypertrophy ( J:74420 )

• by 3 months of age, male and female homozygotes display an increased heart-to-body weight ratio averaging 185% and 133% of wild-type males and females, respectively

• by 4-5 months, homozygotes of both sexes show heart-to-body weight ratios averaging >160% of wild-type, with significantly increased left auricle-to-body weight ratios (250%), right auricle (220%), right ventricle (160%), and left ventricle (150%)

dilated heart left ventricle ( J:74420 )

• by 4-5 months, all homozygotes of both sexes show dilated ventricles, with a mean of >125% wild-type left ventricular end diastolic dimension and end systolic dimensions

• however, left ventricular performance remains intact and no evidence of myocardial dysfunction is observed

dilated heart right ventricle ( J:74420 )

• by 4-5 months, all homozygotes of both sexes display right ventricle-to-body weight ratios averaging >160% of wild-type

cardiac interstitial fibrosis ( J:74420 )

• at 3-5 months, all (4 of 4) male homozygotes display perivascular fibrosis with variable scarring

• in contrast, only 1 of 5 female homozygotes display fibrotic foci at 6 months

abnormal pulmonary circulation ( J:74420 )

• at necropsy, 4 of 8 male homozygotes display congested lungs

pulmonary embolism ( J:74420 )

• 1 of 8 male homozygotes died with external bleeding of unknown origin, also displaying a pulmonary artery luminal inclusion resulting from pulmonary embolism

salt-resistant hypertension ( J:74420 )

• on a low (0.05% NaCl), intermediate (2% NaCl), or high (8% NaCl) salt diet, young adult male and female homozygotes exhibit an average increase in blood pressure of 16 mmHg relative to sex-matched wild-type littermates

• on all three diets, both wild-type and homozygous mutant males display significantly higher blood pressures relative to genotype-matched females (average difference 10 mmHg)

• however, no significant effects of diet on the blood pressures of either sex and of either genotype are detected

congestive heart failure ( J:74420 )

• at necropsy, 4 of 8 male homozygotes display congested hearts

growth/size/body

cardiac hypertrophy ( J:74420 )

• by 3 months of age, male and female homozygotes display an increased heart-to-body weight ratio averaging 185% and 133% of wild-type males and females, respectively

• by 4-5 months, homozygotes of both sexes show heart-to-body weight ratios averaging >160% of wild-type, with significantly increased left auricle-to-body weight ratios (250%), right auricle (220%), right ventricle (160%), and left ventricle (150%)

homeostasis/metabolism

decreased circulating testosterone level ( J:58344 )

• serum testosterone level is 62% lower than in controls

decreased circulating renin level ( J:74420 )

• homozygotes exhibit less than one-third of plasma renin concentration relative to wild-type mice

muscle

abnormal myocardium layer morphology ( J:74420 )

• at 3 to 5 months, male homozygotes with a hypertrophic myocardium show a >200% increase in myocyte cross-sectional area relative to wild-type mice

myocardium necrosis ( J:74420 )

• at 3-5 months, some male homozygotes exhibit patchy areas of incipient myocyte death in the ventricles

respiratory system

abnormal pulmonary circulation ( J:74420 )

• at necropsy, 4 of 8 male homozygotes display congested lungs

pulmonary embolism ( J:74420 )

• 1 of 8 male homozygotes died with external bleeding of unknown origin, also displaying a pulmonary artery luminal inclusion resulting from pulmonary embolism

endocrine/exocrine glands

abnormal sex gland physiology ( J:58344 )

• Leydig cells do not show atrial natriuretic peptide (ANP)-stimulated guanylyl cyclase activation or cGMP accumulation and have no ANP-dependent testosterone production

reproductive system

abnormal sex gland physiology ( J:58344 )

• Leydig cells do not show atrial natriuretic peptide (ANP)-stimulated guanylyl cyclase activation or cGMP accumulation and have no ANP-dependent testosterone production