Analysis Tools
mortality/aging
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• from P3.5 and on, the number of viable mice is significantly lower than expected
• all die before weaning
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growth/size/body
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• about 14% lighter at P0.5
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• by P12.5 mice weigh about 45% of controls
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• between birth and P12.5 mice gain weight slower than wild-type
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behavior/neurological
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• reduced activity
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cardiovascular system
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• at P18, acetylcholine esterase (AChE) staining performed on serial sections of entire hearts revealed a reduction in Purkinje fibers
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• at P18, hearts exhibit reduced expression of connexin 40 (Cx40, a major gap junction protein of the His-bundle and bundle branches ) in the His-bundle compared to wild-type hearts
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• by P12.5 cardiomyocytes became more irregularly shaped
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• a defect in the maturation of intercalated discs, by EM the membranes at the maturing intercalated discs are less convoluted and less wavy
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• by P12.5 cardiomyocytes became smaller in cell width
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• a nonsignificant trend of an increase in the area of left and right ventricle trabecular myocardium compared to wild-type
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• a significant reduction in the area of left and right ventricle compact myocardium
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• noncompaction in right ventricle could be detected at E14.5
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• septal defect in 58% of mice at birth
• defects could be small, large or multiple and found in any location within the muscular septum
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• in 15% of mice at birth
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• at P7.5 and P12.5 wild-type hearts are significantly larger
• however, the heart weight to body weight ratio is increased
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• a reduction in left ventricular internal dimension and volume in both P3.5 and P12 mice during diastole and systole
• a significant reduction in the area of left ventricle compact myocardium and a nonsignificant trend of an increase in the area of left ventricle trabecular myocardium compared to wild-type
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• trend of decrease in compact area and increase in trabecular area were also
observed for right ventricle
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• at P7.5 mutant hearts show slightly reduced cell proliferation
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• exhibit abnormal ventricular filling
• mitral inflow E-wave (early filling) but not A-wave (atrial contraction) peak velocity
is reduced
• E/A ratios are also significantly smaller
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• mice surviving to P20 exhibit a 45% reduction in conduction velocity in left ventricles compared to wild-type controls
• optical mapping revealed that ventricles exhibit slow action potential (AP) propagation
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• at P18, all tested mice show a severe atrioventricular conduction (A-V) block with many P waves followed by missing QRS wave
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• at P14-P17, mice show a significantly prolonged PR interval
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• at P14-P17, mice show a significantly prolonged PR interval and prolonged QT and QTc intervals, but no changes in P wave and QRS interval, suggesting a defect in the infranodal ventricular conduction system
• ventricular myocytes exhibit altered action potential (AP) waveforms, with significantly increased AP amplitude, less negative maximal diastolic potential, and shorter APD at 20%, 50%, and 90% repolarization levels
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• at P14-P17, mice show prolonged QT and QTc intervals
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• the level of apoptosis in P0.5 decreases more slowly and remains significantly higher at P3.5 and P7.5 than in wild-type mice
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• isolated ventricular myocytes exhibit depressed transient outward K+ (ITO) currents and current densities at pulsed voltages from +20 to +60 mV
• the amplitudes and current densities of the outward delayed rectifier K+ current (IK) are significantly increased
• the amplitudes and current densities of the Ba2+-sensitive inward rectifier K+ current (IK1) are significantly increased at negative voltage from -70 to -120 mV
• however, the inward Na+ current (INa) current densities are relatively normal
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liver/biliary system
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• liver weight is significantly reduced between P3.5 and P7.5
• however, the liver weight to body weight ratio is not different than wild-type
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muscle
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• at P18, acetylcholine esterase (AChE) staining performed on serial sections of entire hearts revealed a reduction in Purkinje fibers
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• at P18, hearts exhibit reduced expression of connexin 40 (Cx40, a major gap junction protein of the His-bundle and bundle branches ) in the His-bundle compared to wild-type hearts
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• by P12.5 cardiomyocytes became more irregularly shaped
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• a defect in the maturation of intercalated discs, by EM the membranes at the maturing intercalated discs are less convoluted and less wavy
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• by P12.5 cardiomyocytes became smaller in cell width
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• a nonsignificant trend of an increase in the area of left and right ventricle trabecular myocardium compared to wild-type
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• a significant reduction in the area of left and right ventricle compact myocardium
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• noncompaction in right ventricle could be detected at E14.5
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• the level of apoptosis in P0.5 decreases more slowly and remains significantly higher at P3.5 and P7.5 than in wild-type mice
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integument
cellular
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• the level of apoptosis in P0.5 decreases more slowly and remains significantly higher at P3.5 and P7.5 than in wild-type mice
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homeostasis/metabolism
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• AChE activity (a marker for the ventricular conduction system) is drastically reduced in the endocardial surface of the right ventricle, suggesting improper development of the Purkinje fibers
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