Mouse Genome Informatics
cn1
    Vegfatm2Gne/Vegfatm2Gne
Tg(Tnnt2-cre)5Blh/0

involves: 129/Sv * C57BL/6 * DBA
Key:
phenotype observed in females
phenotype observed in males
N normal phenotype
mortality/aging
• complete lethality is observed after E15.5

growth/size/body
• at E15.5, mutants are runted

cardiovascular system
• at E12.5, the peritruncal area and ventricular septum lack angiogenic sprouts or coronary plexuses that are observed in controls
• by E14.5, mutants have only a few immature myocardial coronary arteries
• dilated subepicardial veins at E14.5
• at E15.5, mutants have necrotic or ruptured septa
• at E15.5, mutants display cardiac hemorrhages


Mouse Genome Informatics
cn2
    Lims1tm1.1Chen/Lims1tm1.1Chen
Lims2tm1.1Chen/Lims2tm1.1Chen
Tg(Tnnt2-cre)5Blh/0

involves: 129/Sv * C57BL/6 * DBA/2
Key:
phenotype observed in females
phenotype observed in males
N normal phenotype
mortality/aging
• mice die within 4 weeks
• mice die within 4 weeks

cardiovascular system
• the pectinate muscles in the atrial appendage is abnormal compared to in wild-type mice
• cultured attached cardiomyocytes are smaller than similarly treated wild-type cells
• round P1
• with a bulge at the base of the right ventricle at P20
• the ventricular walls exhibits irregular thickness with a thickened right ventricular free wall and thin left ventricular free wall and septum compared to in wild-type mice
• at P1, myocardium exhibit widened gaps of intercalated disks with disarrayed sarcomeres and distorted Z lines compared to in wild-type mice
• at P10, membranes of the intercalated disk are highly convoluted and gaps are widened unlike in wild-type mice
• the myocardium exhibits disruption of cell-cell adhesion compared to in wild-type mice
• mice exhibit disorganized trabeculae that fail to fuse and incorporate into compact myocardium unlike in wild-type mice
• at P20
• few cardiomyocytes attack to a plate coated in fibronectin, laminin, and collagen compared with wild-type cells
• progressive, resulting in death

homeostasis/metabolism
• at P20
• extensive in the lungs and liver

liver/biliary system

respiratory system

growth/size/body

muscle
• cultured attached cardiomyocytes are smaller than similarly treated wild-type cells


Mouse Genome Informatics
cn3
    Fgf8tm1.3Mrt/Fgf8tm1.4Mrt
Tg(Tnnt2-cre)5Blh/0

involves: 129P2/OlaHsd * 129S7/SvEvBrd * C57BL/6 * DBA/2
Key:
phenotype observed in females
phenotype observed in males
N normal phenotype
cardiovascular system
N
• no outflow tract or right ventricle defects are observed at E10.5 and no outflow tract septation defects are seen in term fetuses


Mouse Genome Informatics
cn4
    Bmp4tm1Blh/Bmp4tm3.1Blh
Tg(Tnnt2-cre)5Blh/0

involves: 129S/Sv * Black Swiss * C57BL/6 * DBA/2 * ICR
Key:
phenotype observed in females
phenotype observed in males
N normal phenotype
mortality/aging
• no neonates are found

cardiovascular system
• at E12.5 about a 20% decrease in proliferation is detected in the atrioventricular cushions but not in other areas of the heart
• present in 80% of embryos at E15.5 - E16.5
• single atrioventricular junction with a common valve

Mouse Models of Human Disease
OMIM IDRef(s)
Atrioventricular Septal Defect; AVSD 606215 J:86001


Mouse Genome Informatics
cn5
    Pdlim5tm1Chen/Pdlim5tm1Chen
Tg(Tnnt2-cre)5Blh/?

involves: 129S1/Sv * 129X1/SvJ * Black Swiss * C57BL/6 * DBA/2
Key:
phenotype observed in females
phenotype observed in males
N normal phenotype
cardiovascular system
• left ventricular chamber size is significantly enlarged
• develop dilated cardiomyopathy starting at 3 months of age
• left ventricular function significantly impaired as measured by fractional shortening

muscle
• develop dilated cardiomyopathy starting at 3 months of age
• left ventricular function significantly impaired as measured by fractional shortening


Mouse Genome Informatics
cn6
    Cxadrtm1Mds/Cxadrtm1.1Mds
Tg(Tnnt2-cre)5Blh/0

involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * DBA/2
Key:
phenotype observed in females
phenotype observed in males
N normal phenotype
mortality/aging
• no live conditional null mice are found at 4 weeks after birth; embryos at E10.5; mice display identical phenotype to Cxadrtm1.1Mds homozygotes

cardiovascular system
• at E10.5, engorgement of the cardinal veins is apparent
• hyperplasia of proximal heart tube is seen at E10.5
• sinuatrial valves located at junction between sinus venosus and atrium in wild-type embryos, are absent


Mouse Genome Informatics
cn7
    Cxadrtm1Mds/Cxadrtm1Mds
Tg(Tnnt2-cre)5Blh/0

involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * DBA/2
Key:
phenotype observed in females
phenotype observed in males
N normal phenotype
mortality/aging
• no live conditional null mice are found at 4 weeks after birth; embryos at E10.5; mice display identical phenotype to Cxadrtm1.1Mds homozygotes

cardiovascular system
• at E10.5, engorgement of the cardinal veins is apparent
• hyperplasia of proximal heart tube is seen at E10.5
• sinuatrial valves located at junction between sinus venosus and atrium in wild-type embryos, are absent


Mouse Genome Informatics
cn8
    Lims1tm1.1Chen/Lims1tm1.1Chen
Tg(Tnnt2-cre)5Blh/0

involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * DBA/2
Key:
phenotype observed in females
phenotype observed in males
N normal phenotype
cardiovascular system
N
• mice exhibit normal heart morphology and physiology under normal conditions
• following infarct induction
• following infarct induction, mice exhibit reduced fractional shortening and increased infarct size and scar tissue with hemorrhage compared with similarly treated wild-type mice

homeostasis/metabolism
• following infarct induction, mice exhibit reduced fractional shortening and increased infarct size and scar tissue with hemorrhage compared with similarly treated wild-type mice

muscle
• following infarct induction


Mouse Genome Informatics
cn9
    Hand2tm1Cse/Hand2+
Tg(Tnnt2-cre)5Blh/0

involves: 129S1/Sv * C57BL/6J * DBA/2
Key:
phenotype observed in females
phenotype observed in males
N normal phenotype
mortality/aging
• embryos survive at the expected Mendelian ratio until 9.5 dpc, with viablility dropping until 12.5 dpc after which no viable embryos are recovered

cardiovascular system
• at 12.5 dpc, surviving embryos show hypoplastic outflow tract
• at 10.5 dpc severely affected embryos exhibit only a single clearly defined ventricle
• at 12.5 dpc, surviving embryos show hypoplastic right ventricle


Mouse Genome Informatics
cn10
    Bmp4tm3.1Blh/Bmp4tm3.1Blh
Tg(Tnnt2-cre)5Blh/0

involves: 129S6/SvEvTac * C57BL/6 * DBA/2 * ICR
Key:
phenotype observed in females
phenotype observed in males
N normal phenotype
mortality/aging

cardiovascular system
N
• no outflow tract abnormalities are seen
• atrial septal defect similar to that in mice heterozygous for Bmp4tm1Blh and Bmp4tm3.1Blh

Mouse Models of Human Disease
OMIM IDRef(s)
Atrioventricular Septal Defect; AVSD 606215 J:86001


Mouse Genome Informatics
cn11
    Fkbp1atm1.1Shou/Fkbp1atm1Zuk
Tg(Tnnt2-cre)5Blh/0

involves: 129S7/SvEvBrd * C57BL/6 * DBA/2
Key:
phenotype observed in females
phenotype observed in males
N normal phenotype
cardiovascular system
N
• animals show normal ventricular chamber formation; normal trabeculation and compaction in ventricles are observed


Mouse Genome Informatics
cn12
    Smotm2Amc/Smotm2.1Amc
Tg(Tnnt2-cre)5Blh/0

involves: 129X1/SvJ * C57BL/6 * DBA/2
Key:
phenotype observed in females
phenotype observed in males
N normal phenotype
cardiovascular system
N
• mice exhibit normal outflow tract development


Mouse Genome Informatics
cn13
    Cenpftm1Dbdr/Cenpftm1Dbdr
Tg(Tnnt2-cre)5Blh/?

involves: C57BL/6 * DBA/2
Key:
phenotype observed in females
phenotype observed in males
N normal phenotype
cardiovascular system
N
• development of heart structure is grossly normal
• modest reduction in coronary vasculature
• costamere structure is impaired
• decreased number of myocytes in adults
• intercalated disc number is reduced 3.5 fold in mature ventricles
• trabeculae are thinner and blunted
• smaller ventricles
• weight at 4 days of age is 8.2mg compared to 10.5mg for controls
• internal dimension somewhat increased
• modest reduction in epicardial thickness
• cardiac fibrosis in adults
• decreasing ventricular function with age
• three fold decrease in prenatal myocardiocyte proliferation
• P-P intervals greater than 200 ms
• slowing sinus rhythms
• lower myocyte mitotic rates on days 1-4 after birth

growth/size/body
• normal to slightly smaller body size

mortality/aging
• 20% mortality in the 12 to 21 month age period

muscle
• costamere structure is impaired
• decreased number of myocytes in adults
• intercalated disc number is reduced 3.5 fold in mature ventricles
• trabeculae are thinner and blunted
• three fold decrease in prenatal myocardiocyte proliferation

cellular
• three fold decrease in prenatal myocardiocyte proliferation


Mouse Genome Informatics
cx14
    Tarbp2tm1.1Dzw/Tarbp2tm1.1Dzw
Tg(tetO-Mir208a)#Dzw/?
Tg(Tnnt2-cre)5Blh/?

involves: 129 * C3H * C57BL/6 * DBA/2J
Key:
phenotype observed in females
phenotype observed in males
N normal phenotype
cardiovascular system
N
• transgenic expression of Mir208a prevents the onset of dilated cardiomyopathy in cardiac conditional knockouts of Tarbp2 and results in mice with normal heart morphology, histology, and function


Mouse Genome Informatics
cx15
    Tarbp2tm1.1Dzw/Tarbp2tm1.1Dzw
Tg(Tnnt2-cre)5Blh/?

involves: 129 * C57BL/6 * DBA/2J
Key:
phenotype observed in females
phenotype observed in males
N normal phenotype
mortality/aging
• Although homozygotes are born in normal mendelian ratio indicating no embryonic lethality, more than 80 percent of these cardiac conditional knockout homozygotes die by 4 months of age and none survive beyond 8 months of age

cardiovascular system
• although gross morphology of the heart is normal at 2 weeks of age, atrial dilation is found by 3 weeks of age and substantial dilation of both atrial and ventricular chambers is found by 1 month of age and is severe in the homozygotes that survive to 2 months of age, yet cardiomyocyte size appears normal
• neonatal adeno-associated virus-mediated delivery of Tarbp2 or transgenic expression of Mir208a suppresses chamber dilation, permits normal cardiac morphology and restores viability as does knockdown of Sox6, while Tnnt2-dirven viral-mediated overexpression of Sox6 recapitulates the phenotype of cardiac conditional null Tarbp2
• by 3 weeks of age atrial dilation is found
• by 1 month of age dilation of the ventricular chambers is also found
• by 2 weeks of age the left ventricular fractional shortening is decreased and this drops precipitously resulting in severe systolic dysfunction by 1 month of age

muscle
• by 2 weeks of age the left ventricular fractional shortening is decreased and this drops precipitously resulting in severe systolic dysfunction by 1 month of age