Phenotypes Associated with This Genotype

Genotype
MGI:5007651

• Allelic Composition: Tg(Myh6-Tpm1*E180G)57Dfw/0
• Genetic Background: involves: FVB/N

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

mortality/aging

premature death ( J:127507 )

• mutants start to die by 4 months of age, with 70% dying by 5 months of age, and none surviving past 6 months of age

• average age of death is 4 months 24 days

cardiovascular system

abnormal myocardial fiber morphology ( J:127507 )

• myofibrillar disorganization is seen in up to 25% of the ventricular wall

increased heart atrium size ( J:127507 , J:172340 )

• by 2 months of age, mutants exhibit an increase in the size of the left and right atria (J:127507)

abnormal heart septum morphology ( J:127507 )

• mutants exhibit a increase in septal wall thickness

cardiac hypertrophy ( J:127507 , J:171021 , J:172340 )

• cardiac hypertrophy as indicated by an increase in the percentage heart weight: body weight ratio (J:127507)

• by 3 months of age, mutants exhibit an increase in heart size, particularly in the left and right atria (J:172340)

abnormal heart ventricle morphology ( J:172340 )

• myofibrillar disorganization is seen in 25% of the ventricular walls

abnormal heart left ventricle morphology ( J:127507 )

• at 3 months of age, the left ventricular wall shows increased numbers of interstitial cells, disorganization of myocytes, and increased fibrosis

heart left ventricle hypertrophy ( J:127507 )

• by 2 months of age, mutants exhibit an increase in the size of the left ventricle

• concentric left ventricular hypertrophy associated with isolated diastolic dysfunction

cardiac fibrosis ( J:127507 , J:172340 )

• fibrosis involves 5-10% of the ventricular wall (J:127507)

• fibrosis in the left ventricular walls (J:172340)

abnormal diastolic filling velocity ( J:127507 )

• Doppler echocardiography in 3 month old mutants shows a greater diastolic transmitral early to late velocity ratio (E/A) compared to controls, correlating with more congestive symptoms

• the ratio of systolic to diastolic pulmonary vein flow (S/D) and the propagation velocity of transmitral flow on color M-mode (Vp) is less in mutants than controls, indicating impaired diastolic filling and elevated left atrial pressure

• however, left ventricular fractional shortening and the velocity of circumferential shortening (systolic function) are normal

abnormal cardiac muscle contractility ( J:127507 , J:172340 )

• rate of contraction in early stage hearts is slightly increased, although it is not significant (J:127507)

• 4.5-month old hearts are hypodynamic in both contractile and relaxation function in response to isoproterenol (J:127507)

• inotropic stimulation with the beta-adrenergic agonist, isoproterenol, is impaired (J:172340)

decreased cardiac muscle contractility ( J:171021 )

• hearts do not exhibit an increase in contractility as the heart rate is increased and cannot be efficiently paced beyond 50-55 bpm

increased cardiac muscle contractility ( J:172340 )

• the maximal rate of pressure development for contraction (+dP/dt) is increased in mutants, indicating increased contractility

abnormal cardiac muscle relaxation ( J:127507 , J:172340 )

• rate of relaxation in early stage hearts is decreased (J:127507)

• 4.5-month old hearts are hypodynamic in both contractile and relaxation function in response to isoproterenol (J:127507)

• maximal rate of pressure decline (-dP/dt) is decreased in mutants hearts, indicating impaired relaxation (J:172340)

• the half time of relaxation or the time from the peak intraventricular pressure to the point of 50% ventricular relaxation is longer than that of control mice, indicating that left ventricular relaxation is severely compromised (J:172340)

increased left ventricle diastolic pressure ( J:127507 , J:172340 )

• end-diastolic and diastolic pressures are increased, indicating diastolic dysfunction (J:127507)

• heart shows increased diastolic pressure (J:172340)

decreased heart rate ( J:171021 )

• during beta-adrenergic stimulation via infusion of dobutamine, heart rate is reduced in mutants compared with wild-type mice

abnormal myocardial fiber physiology ( J:127507 )

• skinned fiber bundles from 2.5 month old mutants show that myofilaments have an increase in calcium sensitivity and an increase in maximum tension generation; these differences are seen in both long and short sarcomere lengths, however increase in calcium sensitivity is sarcomere length dependent

muscle

abnormal myocardial fiber morphology ( J:127507 )

• myofibrillar disorganization is seen in up to 25% of the ventricular wall

heart left ventricle hypertrophy ( J:127507 )

• by 2 months of age, mutants exhibit an increase in the size of the left ventricle

• concentric left ventricular hypertrophy associated with isolated diastolic dysfunction

abnormal cardiac muscle contractility ( J:127507 , J:172340 )

• rate of contraction in early stage hearts is slightly increased, although it is not significant (J:127507)

• 4.5-month old hearts are hypodynamic in both contractile and relaxation function in response to isoproterenol (J:127507)

• inotropic stimulation with the beta-adrenergic agonist, isoproterenol, is impaired (J:172340)

decreased cardiac muscle contractility ( J:171021 )

• hearts do not exhibit an increase in contractility as the heart rate is increased and cannot be efficiently paced beyond 50-55 bpm

increased cardiac muscle contractility ( J:172340 )

• the maximal rate of pressure development for contraction (+dP/dt) is increased in mutants, indicating increased contractility

abnormal cardiac muscle relaxation ( J:127507 , J:172340 )

• rate of relaxation in early stage hearts is decreased (J:127507)

• 4.5-month old hearts are hypodynamic in both contractile and relaxation function in response to isoproterenol (J:127507)

• maximal rate of pressure decline (-dP/dt) is decreased in mutants hearts, indicating impaired relaxation (J:172340)

• the half time of relaxation or the time from the peak intraventricular pressure to the point of 50% ventricular relaxation is longer than that of control mice, indicating that left ventricular relaxation is severely compromised (J:172340)

homeostasis/metabolism

abnormal atrial thrombosis ( J:127507 )

• large thrombi are often present in the enlarged left and right atria

abnormal calcium ion homeostasis ( J:171021 )

• amplitude of the calcium transient is reduced in myocytes and time to 50% decay of the calcium transient is greater in myocytes, indicating impaired calcium handling compared to wild-type myocytes

respiratory system

increased lung weight ( J:171021 )

• increase in left lung weight/body weight ratio

behavior/neurological

lethargy ( J:127507 )

growth/size/body

cardiac hypertrophy ( J:127507 , J:171021 , J:172340 )

• cardiac hypertrophy as indicated by an increase in the percentage heart weight: body weight ratio (J:127507)

• by 3 months of age, mutants exhibit an increase in heart size, particularly in the left and right atria (J:172340)

heart left ventricle hypertrophy ( J:127507 )

• by 2 months of age, mutants exhibit an increase in the size of the left ventricle

• concentric left ventricular hypertrophy associated with isolated diastolic dysfunction

increased lung weight ( J:171021 )

• increase in left lung weight/body weight ratio

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
hypertrophic cardiomyopathy 3		DOID:0110309	OMIM:115196	J:127507 , J:171021 , J:172340