Phenotypes Associated with This Genotype

Genotype
MGI:5909088

• Allelic Composition: Tg(Myh7-Ptpn11*Q510E)#Krnz/0
• Genetic Background: FVB/N-Tg(Myh7-Ptpn11*Q510E)#Krnz

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

cardiovascular system

abnormal myocardial fiber morphology ( J:222124 )

• the relative area per visual field occupied by sarcomeres under electron microscopy is increased, indicating that more thin and thick filaments per cardiomyocyte width (increase in assembled contractile myofibers) may be available for force generation

• however, no difference in sarcomere organization or length is seen in 4 week old cardiomyocytes

increased myocardial fiber size ( J:181656 , J:222124 )

• 4 week old cardiomyocytes exhibit cellular hypertrophy with an 18% increase in cell length and a 49% increase in cell width (J:222124)

myocardial fiber disarray ( J:181656 )

• in older mice, the extent of disarray is increased compared with newborn hearts

fetal cardiomyocyte disarray ( J:181656 )

• cardiomyocyte disarray is seen in newborn hearts, with disarray increased in older mice

increased fetal cardiomyocyte size ( J:181656 )

• cardiomyocyte size is increased in newborns

• cardiomyocyte size is normalized in pups from nursing dams administered rapamycin starting after delivery

increased heart atrium size ( J:181656 )

• enlarged atria at birth

increased heart left atrium size ( J:181656 )

♂ • left atrial diameters are increased by 37% in 3 month old males

thick interventricular septum ( J:181656 )

• interventricular septum is thickened in 1 day old mice

• interventricular septum is 1.4-fold thicker in 2 week old hearts and septum thickness remains increased at 3 months of age

• however, interventricular septum and free wall thickness are normal at E13.5

• rapamycin delivery to pups via maternal milk normalizes septum thickness

ventricular septal defect ( J:181656 )

• small membraneous or muscular ventricular septal defects are seen in about 50% of hearts at 1 day of age

abnormal heart ventricle shape ( J:181656 )

• both the left ventricle and right ventricle exhibit a rounded shape at birth

• ventricles display a round shape already at E13.5

increased heart weight ( J:181656 , J:222124 )

• heart-to-body weight ratios are increased by 32% (J:181656)

• rapamycin delivery to pups via maternal milk abolishes the increased heart weight (J:181656)

• heart weight, heart-to-body weight, and ventricular weight-to-tibia ratios are increased in both males and females at 4 weeks of age (J:222124)

cardiac hypertrophy ( J:181656 , J:222124 )

• neonatal-onset (J:181656)

abnormal interventricular groove morphology ( J:181656 )

• interventricular groove is enhanced at birth

cardiac interstitial fibrosis ( J:181656 )

• mild interstitial fibrosis is first seen at 3 months of age

• isolated foci of fibrosis are seen in the septum, in the left ventricle free wall and in the apex and fibrosis is increased in the perivascular regions

decreased heart left ventricle muscle contractility ( J:181656 )

♂ • left ventricular fractional shortening is depressed by 20% in 3 month old males

increased cardiac muscle contractility ( J:222124 )

• 4-6 week old mice show enhanced contractile function with increased ejection fraction and fractional shortening

• skinned cardiac myofibers exhibit increased force and power generation indicating that sarcomeric contractile function is increased

abnormal heart echocardiography feature ( J:181656 , J:222124 )

• echocardiography in 4-6 week old mice under isoflurane anesthesia shows enhanced contractile function with increased ejection fraction and fractional shortening (J:222124)

♂ • echocardiography indicates 37% increase in left atrial diameters, 20% depression of left ventricular fractional shortening, and 29% and 22% increase in end-diastolic dimensions of the interventricular septum and left ventricle posterior wall, respectively, in 3 month old males (J:181656)

♂ • mice treated with rapamycin from 6-10 weeks of age show septum and left ventricular posterior wall dimension normalization (J:181656)

abnormal myocardial fiber physiology ( J:222124 )

• calcium transient amplitude is higher in insolated cardiomyocytes of 4 week old mutants at all stimulation frequencies indicating enhanced calcium transients during excitation-contraction coupling in cardiomyocytes

• sarcoplasmic reticulum calcium content is elevated in 4 week old cardiomyocytes when caffeine is applied after cessation of a 0.5-Hz stimulation train

• skinned cardiac myofibers exhibit increased force and power generation indicating that sarcomeric contractile function is increased

cardiomyopathy ( J:181656 )

• mice exhibit a neonatal-onset hypertrophic cardiomyopathy

muscle

abnormal myocardial fiber morphology ( J:222124 )

• the relative area per visual field occupied by sarcomeres under electron microscopy is increased, indicating that more thin and thick filaments per cardiomyocyte width (increase in assembled contractile myofibers) may be available for force generation

• however, no difference in sarcomere organization or length is seen in 4 week old cardiomyocytes

increased myocardial fiber size ( J:181656 , J:222124 )

• 4 week old cardiomyocytes exhibit cellular hypertrophy with an 18% increase in cell length and a 49% increase in cell width (J:222124)

myocardial fiber disarray ( J:181656 )

• in older mice, the extent of disarray is increased compared with newborn hearts

decreased heart left ventricle muscle contractility ( J:181656 )

♂ • left ventricular fractional shortening is depressed by 20% in 3 month old males

increased cardiac muscle contractility ( J:222124 )

• 4-6 week old mice show enhanced contractile function with increased ejection fraction and fractional shortening

• skinned cardiac myofibers exhibit increased force and power generation indicating that sarcomeric contractile function is increased

cardiomyopathy ( J:181656 )

• mice exhibit a neonatal-onset hypertrophic cardiomyopathy

growth/size/body

increased heart weight ( J:181656 , J:222124 )

• heart-to-body weight ratios are increased by 32% (J:181656)

• rapamycin delivery to pups via maternal milk abolishes the increased heart weight (J:181656)

• heart weight, heart-to-body weight, and ventricular weight-to-tibia ratios are increased in both males and females at 4 weeks of age (J:222124)

cardiac hypertrophy ( J:181656 , J:222124 )

• neonatal-onset (J:181656)

cellular

cardiac interstitial fibrosis ( J:181656 )

• mild interstitial fibrosis is first seen at 3 months of age

• isolated foci of fibrosis are seen in the septum, in the left ventricle free wall and in the apex and fibrosis is increased in the perivascular regions

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
hypertrophic cardiomyopathy		DOID:11984		J:181656
Noonan syndrome with multiple lentigines		DOID:14291	OMIM:PS151100	J:222124