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Phenotypes associated with this allele
Allele Symbol
Allele Name
Allele ID
Hey2tm1Kkb
targeted mutation 1, Hiroki Kokubo
MGI:3574394
Summary 2 genotypes
Jump to Allelic Composition Genetic Background Genotype ID
hm1
Hey2tm1Kkb/Hey2tm1Kkb involves: 129S7/SvEvBrd * C57BL/6 MGI:3620804
cx2
Hey1tm1Kkb/Hey1tm1Kkb
Hey2tm1Kkb/Hey2tm1Kkb
involves: 129S7/SvEvBrd * C57BL/6 MGI:3574774


Genotype
MGI:3620804
hm1
Allelic
Composition
Hey2tm1Kkb/Hey2tm1Kkb
Genetic
Background
involves: 129S7/SvEvBrd * C57BL/6
Find Mice Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Hey2tm1Kkb mutation (1 available); any Hey2 mutation (19 available)
phenotype observed in females
phenotype observed in males
N normal phenotype
mortality/aging
• most homozygotes die within the first 10 days after birth as a result of congestive heart failure
• morbidity rate at 2 to 7 months of age is 57.1% in mice that survive the postnatal period

cardiovascular system
• at P5, homozygotes display congested livers
• however, bile ducts remain normal
• at P5, homozygotes exhibit pulmonary congestion
• at P5, homozygotes display dysplastic mitral valves relative to heterozygous mutant mice
• at P5, homozygotes display dysplastic tricuspid valves relative to heterozygous mutant mice
• at P5, the orifice of the mutant tricuspid valve is significantly smaller than that of the mitral valve
• at P5, homozygotes exhibit a histologically obvious secundum atrial septal defect
• at P5, both the left and right atria are enlarged
• at P5, homozygotes exhibit thickening of the endocardium of the left atrium and left ventricle, with more elastin fibers and collagen fibers relative to heterozygous mutant mice
• fibrosis in the myocardium that worsens with age in surviving mice
• at P5, mutant cardiomyocytes contain fewer, disorganized myofibrils, vacuolized and aberrantly shaped mitochondria, and numerous glycogen particles in the absence of myocyte hypertrophy or cardiomyopathy (J:97120)
• cardiomyocytes show slightly thickened Z-discs and higher numbers of mitochondria and golgi bodies (J:216895)
• cardiomyocyte degeneration with age (J:216895)
• width of myocardial cells in the ventricles are larger than in wild-type mice, becoming more prominent with age
• at P5, pulsed-wave Doppler echocardiograms exhibit high-velocity, broad, and upward waveforms during systole, indicating flow through a VSD; histology confirms the presence of a perimembranous VSD
• at P5, the mutant heart occupies almost the entire thoracic cavity; a normal d-ventricular loop is observed
• at P5, homozygotes show a significantly increased ratio of heart weight to body weight
• sclerotic degeneration, including thickening, fibrosis and accumulation of glycosaminoglycans and reduced collagen-I, but not calcification, develops in the semilunar valves after birth and is seen in mutants that survive the postnatal period (J:216895)
• at P5, the mutant aortic valves have 3 leaflets, as expected; however, these leaflets appear relatively dysplastic
• ratio of mice with aortic stenosis and regurgitation increase to 58.8% until more than 12 months of age
• develops after birth
• at P5, the mutant pulmonary valves have 3 leaflets, as expected; however, these leaflets appear relatively dysplastic
• develops after birth
• at P5, homozygotes exhibit a significantly dilated left ventricular chamber (J:97120)
• homozygous mutant LV internal dimensions at end-diastole and end-systole are larger than those in heterozygous mice (J:97120)
• left ventricle internal dimension at systole and diastole is higher than in wild-type mice at 12 months of age (J:216895)
• 1 month old mice with aortic valve stenosis and regurgitation show severe thickening with fibrosis in the pulmonary and aortic valve leaflets, whereas mice without stenosis/regurgitation show slight thickening but not fibrosis in the aortic valve leaflets
• fibrosis is seen in border regions of the pulmonary and aortic valves of 2-3 month old mice, however calcification is rarely seen
• at P5, homozygotes exhibit a significantly reduced fractional shortening of the left ventricle relative to heterozygous mutant mice (~38% vs ~50%, respectively), indicating impaired LV systolic function (J:97120)
• in contrast, LV diastolic function remains unaffected, as shown by a normal E wave/A wave ratio, and aortic and pulmonary outflow tracts display normal waveform patterns (J:97120)
• left ventricular fractional shortening is reduced (less than 23%) in about 41% of 12 month old mutants, indicating a decrease in left ventricle systolic function (J:216895)
• at P5, homozygotes exhibit AV valve regurgitation caused by dysplastic AV valves
• at P5, transthoracic echocardiography indicates severe mitral valve regurgitation, with downward regurgitant jets noted at the mitral orifice during systole
• at P5, transthoracic echocardiography indicates tricuspid valve regurgitation, with waveforms in the downward direction noted at the tricuspid orifice during systole
• during diastole, abnormal downward and wide waveforms are seen at the aortic valve indicating regurgitation
• ratio of mice with aortic stenosis and regurgitation increase to 58.8% until more than 12 months of age
• homozygotes exhibit a 15% reduction in heart rate relative to heterozygous mutant mice (312 31 vs 368 12, respectively)
• most homozygotes die as a result of congestive heart failure

growth/size/body
• at P5, most homozygotes exhibit growth retardation relative to wild-type mice

respiratory system
• at P5, homozygotes exhibit pulmonary congestion
• at P5, homozygotes exhibit pulmonary edema
• at P5, homozygotes show a significantly increased ratio of lung weight to body weight
• at P5, homozygotes exhibit collapse of some alveoli
• authors propose that pulmonary congestion and alveolar collapse ultimately cause heart failure and dyspnea leading to death

muscle
• at P5, mutant cardiomyocytes contain fewer, disorganized myofibrils, vacuolized and aberrantly shaped mitochondria, and numerous glycogen particles in the absence of myocyte hypertrophy or cardiomyopathy (J:97120)
• cardiomyocytes show slightly thickened Z-discs and higher numbers of mitochondria and golgi bodies (J:216895)
• cardiomyocyte degeneration with age (J:216895)
• at P5, homozygotes exhibit a significantly reduced fractional shortening of the left ventricle relative to heterozygous mutant mice (~38% vs ~50%, respectively), indicating impaired LV systolic function (J:97120)
• in contrast, LV diastolic function remains unaffected, as shown by a normal E wave/A wave ratio, and aortic and pulmonary outflow tracts display normal waveform patterns (J:97120)
• left ventricular fractional shortening is reduced (less than 23%) in about 41% of 12 month old mutants, indicating a decrease in left ventricle systolic function (J:216895)
• cardiomyocytes show slightly thickened Z-discs

homeostasis/metabolism
• at P5, homozygotes exhibit pulmonary edema

liver/biliary system
• at P5, homozygotes display congested livers
• however, bile ducts remain normal

Mouse Models of Human Disease
DO ID OMIM ID(s) Ref(s)
aortic valve disease DOID:62 J:216895




Genotype
MGI:3574774
cx2
Allelic
Composition
Hey1tm1Kkb/Hey1tm1Kkb
Hey2tm1Kkb/Hey2tm1Kkb
Genetic
Background
involves: 129S7/SvEvBrd * C57BL/6
Find Mice Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Hey1tm1Kkb mutation (0 available); any Hey1 mutation (9 available)
Hey2tm1Kkb mutation (1 available); any Hey2 mutation (19 available)
phenotype observed in females
phenotype observed in males
N normal phenotype
mortality/aging

cardiovascular system
• the cell layers surrounding the arteries are thinner
• the putative dorsal aorta lacks expression of smooth muscle actin and Ephrin-B2 suggesting failure of arterial differentiation
• the putative dorsal aorta lacks expression of smooth muscle actin and Ephrin-B2 suggesting failure of arterial differentiation
• at E9.5 cardiac endothelial cell transformation does not occur in the AV cushion despite enrichment of the extracellular matrix
• the heart chambers fails to divide resulting in a single atria and ventricles at E10.5
• however, right-left polarity is established
• the AV cushions are not properly formed at E10.5
• only a single atria is present at E10.5
• the cardiomyocytes are disorganized with fewer myofibrils and swollen and irregular mitochondria
• the trabecular zone is not properly formed at E10.5
• hypoplastic trabeculae are seen in the single open atria and ventricle
• initial formation of the trabecular zone is normal however more apoptotic cells are seen compared to double heterozygous littermates at E10
• only a single ventricle is present at E10.5
• seen at E10.5

embryo
• the first pharyngeal arches are smaller at E10.5
• the second pharyngeal arches are smaller at E10.5
• at E10.5 large blood vessels fail to form in the yolk sac; however, small blood vessels are present

muscle
• the cardiomyocytes are disorganized with fewer myofibrils and swollen and irregular mitochondria
• the trabecular zone is not properly formed at E10.5
• hypoplastic trabeculae are seen in the single open atria and ventricle
• initial formation of the trabecular zone is normal however more apoptotic cells are seen compared to double heterozygous littermates at E10

nervous system
• at E10.5 the telencephalic regions are poorly formed

craniofacial
• the first pharyngeal arches are smaller at E10.5
• the second pharyngeal arches are smaller at E10.5





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last database update
01/09/2018
MGI 6.11
The Jackson Laboratory