Analysis Tools
mortality/aging
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• surviving homozygotes grow normally, are fertile and produce litters of normal size; however, 43% of adult male and female homozygotes die within 12 months
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• only 40% of homozygotes survive to weaning
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cardiovascular system
dilated aorta
(
J:83820
)
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• at 5 months, homozygotes display aortic dilation, a classic symptom of valvular stenosis
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• mutant AV valves fail to undergo remodeling and form slender valve leaflets, and are only modestly reduced in size remaining 36-46% larger than wild-type counterparts through E15.5
• impaired remodeling of mutant AV valves is due to a ~3.5-fold increase in mesenchymal cell proliferation at E14.5 or later, and is associated with dramatic increases in activated Smad1/5/8
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• mutant PV valves fail to undergo remodeling and form slender valve leaflets, and are only modestly reduced in size remaining 36-46% larger than wild-type counterparts through E15.5
• impaired remodeling of mutant PV valves is due to a ~2-fold increase in mesenchymal cell proliferation at E14.5 or later, and is associated with dramatic increases in activated Smad1/5/8
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• all newborn homozygotes display stenotic atrioventricular valves
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• all newborn homozygotes display enlarged atrioventricular valves
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• at necropsy, homozygotes that die within the first year of life exhibit enlarged hearts and congested lungs, in the absence of other pathological defects
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• male homozygotes show a continuous increase in heart-to-body weight ratios from birth through 6 months of age, with the largest relative increase noted between 3 and 6 weeks
• at 6 weeks, the mean heart-to-body weight ratio for mutant mice is 1.27 +/- 0.20% vs 0.80 +/- 0.03% for wild-type mice
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• all newborn homozygotes display enlarged semilunar valves
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• at birth, the mean area of mutant aortic valves is 56.7 +/- 17 mm2 relative to 21.9 +/- 4.6 mm2 in wild-type
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• all newborn homozygotes display stenotic semilunar valves
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• at 5 months, male homozygotes exhibit reduced fractional shortening (51.6 +/- 7.4) relative to wild-type males (68.7 +/- 2.7), indicating significant systolic dysfunction
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muscle
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• at 5 months, male homozygotes exhibit reduced fractional shortening (51.6 +/- 7.4) relative to wild-type males (68.7 +/- 2.7), indicating significant systolic dysfunction
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respiratory system
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• ~50% of mutant lungs exhibit significantly fewer alveoli than wild-type lungs (39.2 +/- 4.0 vs 28.1 +/- 6.7 per field)
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• ~50% of newborn homozygotes exhibit hypoplastic, poorly differentiated lungs
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• ~50% of newborn homozygotes display thickened mesenchymal tissue between alveoli
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• PAS staining indicates a high fraction of immature, glycogen-containing cells in newborn mutant lungs; conversely, fewer cells in mutant lungs stain positive for type II pneumocyte marker pro-surfactant C
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skeleton
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• homozygotes display chondrocytes and ectopic cartilage formation throughout the aortic valve leaflets possibly as a result of disregulated BMP signaling in cardiac tissue
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growth/size/body
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• at necropsy, homozygotes that die within the first year of life exhibit enlarged hearts and congested lungs, in the absence of other pathological defects
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• male homozygotes show a continuous increase in heart-to-body weight ratios from birth through 6 months of age, with the largest relative increase noted between 3 and 6 weeks
• at 6 weeks, the mean heart-to-body weight ratio for mutant mice is 1.27 +/- 0.20% vs 0.80 +/- 0.03% for wild-type mice
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