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Allele Symbol Allele Name Allele ID |
Myh6tm1Jse targeted mutation 1, Jonathan G Seidman MGI:2182704 |
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| Summary |
7 genotypes
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• by P6, all homozygotes exhibit myocardial necrosis
• myocardial necrosis is moderate to severe in 14 of 15 homozygotes
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• homozygotes are liveborn but show a progressive decline in survival after P5
• no homozygotes live beyond P8
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• at P0, homozygotes show normal myocardial histology and prevalence of mitoses; by P6, mutants show diffuse mild-to-moderate cardiomyocyte hypertrophy with lesions of focal necrosis involving several contiguous myocytes or multifocal, confluent, and transmural necrosis
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• at P6, mutant hearts display normal ultrastructural architecture intermixed with focal myofibrillar disarray
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• focal myofibrillar disarray at P6
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• by P6, all homozygotes exhibit myocardial necrosis
• myocardial necrosis is moderate to severe in 14 of 15 homozygotes
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• at P6, homozygotes display dilation of both atria
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• at P4, homozygotes display LV wall thinning
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• at P6, homozygotes exhibit LV dilation and discoloration
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• at P4-P6, homozygotes develop a rapidly progressive and lethal dilated cardiomyopathy
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• by P6, 87% of homozygotes exhibit secondary dystrophic calcification
• dystrophic calcification is moderate to severe in 9 of 13 homozygotes
• no homozygotes display calcification in the absence of necrosis
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• by P6, all homozygotes display a global reduction of systolic contraction and/or LV dilation
• 45-MHz echocardiography revealed biventricular failure in 50% of homozygotes with LA, LV, and RV dilatation and pericardial effusion
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• at P6, homozygotes with LV dilation and contractile dysfunction exhibit thrombus formation in the dilated left atrium
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• at P0, homozygotes show normal myocardial histology and prevalence of mitoses; by P6, mutants show diffuse mild-to-moderate cardiomyocyte hypertrophy with lesions of focal necrosis involving several contiguous myocytes or multifocal, confluent, and transmural necrosis
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• focal myofibrillar disarray at P6
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• at P6, mutant hearts display normal ultrastructural architecture intermixed with focal myofibrillar disarray
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• myocardial necrosis is moderate to severe in 14 of 15 homozygotes
• by P6, all homozygotes exhibit myocardial necrosis
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• at P4-P6, homozygotes develop a rapidly progressive and lethal dilated cardiomyopathy
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• by P6, all homozygotes display a global reduction of systolic contraction and/or LV dilation
• 45-MHz echocardiography revealed biventricular failure in 50% of homozygotes with LA, LV, and RV dilatation and pericardial effusion
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
Myocyte disarray and cardiac fibrosis in Myh6tm1Jse/Myh6+ mice
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• myocyte disarray is seen in 29% of young and 40% of adult mutants, usually in the left ventricular wall or interventricular septum
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• develop cardiac hypertrophy with increasing age such that by 20-30 weeks of age, hypertrophy is uniformly present
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• mutants with inducible arrhythmias have greater left ventricular wall thickness and greater hypercontractility than mutants without inducible arrythmias, however observe no correlation between wall thickness and amount of fibrosis or myocyte disarray
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• develop difusse and focal cardiac fibrosis with increasing age; total amount of fibrosis within each heart varies broadly
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• end-diastolic left ventricle dimensions are smaller and fractional shortening is increased
• mutants with inducible arrhythmias have greater hypercontractility than mutants without inducible arrythmias
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• ventricular tachyarrhythmia is induced in 25% of young and 69% of adults by rapid ventricular pacing at a cycle length of more than or equal to 50 ms; no arrhythmias are induced in wild-type
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• develop cardiac hypertrophy with increasing age such that by 20-30 weeks of age, hypertrophy is uniformly present
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• myocyte disarray is seen in 29% of young and 40% of adult mutants, usually in the left ventricular wall or interventricular septum
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• end-diastolic left ventricle dimensions are smaller and fractional shortening is increased
• mutants with inducible arrhythmias have greater hypercontractility than mutants without inducible arrythmias
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Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| hypertrophic cardiomyopathy 14 | DOID:0110320 |
OMIM:613251 |
J:104363 | |
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• reduced tolerance for vigorous exercise in swimming tests
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• histological changes in heart tissue more consistent in males than females
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• hypertrophy of myocytes with large hyperchromatic nuclei by 30 weeks of age
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• myocardial fiber disarray becoming marked by 30 weeks of age
(J:32960)
• slight myocyte disarray is noticeable in tissue from apex of mutant hearts at 10-20 weeks of age
(J:95600)
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• some individuals with left atrial enlargement at 15 weeks of age, particularly among males
• left atrial enlargement more prevalent by 30 weeks of age, 100% of males and a third of females
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• apexes of 2/4 mutant hearts have undergone slight but noticeable fibrosis and myocyte disarray compared to wild-type hearts
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• moderate diffuse interstitial fibrosis by 30 weeks of age, starting as early as 15 weeks
• focal replacement granulation tissue at 30 weeks
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• discontinuous pressure change with ventricular relaxation
(J:32960)
• end diastolic pressure reduced with increased Calcium concentration during heart perfusion although systolic pressure is normal
(J:47028)
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• longer duration of relaxation
(J:32960)
• maximal rate of relaxation reduced
(J:47028)
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• mutants show marked differences in cross-bridge kinetics of isolated myosin and skinned strips of myocardium
• maximal velocity (V) of regulated thin filament (RTF) in an in vitro motility assay is increased by 8% in mutants vs wild-type
• myosin concentration at half-maximal VRTF is reduced by 30% compared to wild-type
• characteristic frequency for oscillatory work production in skinned strips is 27% lower in mutants vs wild-type
• calcium sensitivity for isometric tension in skinned strips is comparable to wild-type
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• hypertrophy of myocytes with large hyperchromatic nuclei by 30 weeks of age
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• myocardial fiber disarray becoming marked by 30 weeks of age
(J:32960)
• slight myocyte disarray is noticeable in tissue from apex of mutant hearts at 10-20 weeks of age
(J:95600)
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• isolated myosin from 10-20 week-old mutant hearts shows a 38% increase in Vmax of actin-activated ATP hydrolysis (ATPase) compared to wild-type
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• moderate diffuse interstitial fibrosis by 30 weeks of age, starting as early as 15 weeks
• focal replacement granulation tissue at 30 weeks
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Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| hypertrophic cardiomyopathy 14 | DOID:0110320 |
OMIM:613251 |
J:32960 , J:95600 | |
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• cyclosporine A-treated mice exhibit reduced myocardial fibrosis than in similarly treated Myh6tm1Jse homozygotes
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• cyclosporine A-treated mice exhibit a 2.4-fold reduction in non-myocyte cell proliferation compared with similarly treated Myh6tm1Jse homozygotes but remains higher than in similarly treated wild-type mice
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• cyclosporine A-treated mice exhibit a modest, but not significantly, reduction in maximal left ventricular wall thickness compared with similarly treated Myh6tm1Jse homozygotes
• cyclosporine A-treated mice exhibit reduced myocardial fibrosis than in similarly treated Myh6tm1Jse homozygotes
• cyclosporine A-treated mice exhibit a 2.4-fold reduction in non-myocyte cell proliferation compared with similarly treated Myh6tm1Jse homozygotes but remains higher than in similarly treated wild-type mice
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• 100% mortality by 21 days of age, with survival declining rapidly from 16 days of age
• mean life span of males is 16.8 days, while the mean life span of females is 18.3 days
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• abnormal myofiber alignment
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• altered alignment of myofibrils, myocyte atrophy and fragmentation, altered distribution of mitochondria between myofibrils, myofibril disarray and discontinuity, degeneration and loss of myocyte structure, collagen accumulation, greater infiltration of other cells, and enlarged extracellular spaces
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• cardiomyocyte hypertrophy
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• degeneration and loss of cardiac myocyte structure
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• areas of necrosis in left ventricular myocardium
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• increase in heart weight to body weight ratio at 14 and 16 days of age
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• 4-chamber cardiac enlargement at 14 days of age
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• biatrial dilatation
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• mice develop severe dilated cardiomyopathy, with enlargement of left ventricular cardiac chambers and a reduction in fractional shortening
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• reduction in cardiac function at 16 to 18 days of age, with decreased fractional shortening which is reduced to below 20% in some mice
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• increase in left ventricular end-diastolic and end-systolic diameter
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• at 14 days of age
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• adrenaline administration induces ventricular arrhythmias in some mice
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• first degree atrioventricular block
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• at 14 days of age
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• increase in P-wave height
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• the corrected QT interval is increased
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• premorbid left atrial thrombus is seen in a subgroup of hearts
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• abnormal myofiber alignment
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• altered alignment of myofibrils, myocyte atrophy and fragmentation, altered distribution of mitochondria between myofibrils, myofibril disarray and discontinuity, degeneration and loss of myocyte structure, collagen accumulation, greater infiltration of other cells, and enlarged extracellular spaces
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• cardiomyocyte hypertrophy
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• degeneration and loss of cardiac myocyte structure
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• areas of necrosis in left ventricular myocardium
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• mice develop severe dilated cardiomyopathy, with enlargement of left ventricular cardiac chambers and a reduction in fractional shortening
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• reduction in cardiac function at 16 to 18 days of age, with decreased fractional shortening which is reduced to below 20% in some mice
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• ratio of lung weight to body weight is increased
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• increase in heart weight to body weight ratio at 14 and 16 days of age
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• ratio of lung weight to body weight is increased
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• areas of necrosis in left ventricular myocardium
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Mouse Models of Human Disease |
DO ID | OMIM ID(s) | Ref(s) | |
| hypertrophic cardiomyopathy | DOID:11984 | J:153302 | ||
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| ♀ | phenotype observed in females |
| ♂ | phenotype observed in males |
| N | normal phenotype |
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• improved compared with Tg(Myh6/tetO-Tnnc1*I61Q)1Jmol mice
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• improved compared with Tg(Myh6/tetO-Tnnc1*I61Q)1Jmol mice
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• improved compared with Tg(Myh6/tetO-Tnnc1*I61Q)1Jmol mice
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• improved compared with Tg(Myh6/tetO-Tnnc1*I61Q)1Jmol mice
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• mice exhibit improved fractional shortening compared with Tg(Myh6/tetO-Tnnc1*I61Q)1Jmol mice
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• mice exhibit improved fractional shortening compared with Tg(Myh6/tetO-Tnnc1*I61Q)1Jmol mice
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• improved compared with Tg(Myh6/tetO-Tnnc1*I61Q)1Jmol mice
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Mouse Genome Database (MGD), Gene Expression Database (GXD), Mouse Models of Human Cancer database (MMHCdb) (formerly Mouse Tumor Biology (MTB)), Gene Ontology (GO) |
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last database update 04/23/2024 MGI 6.23 |
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