Phenotypes associated with this allele

• Allele Symbol: Med12^tm1.1Hsch
• Allele Name: targeted mutation 1.1, Heinrich Schrewe
• Allele ID: MGI:4839485
• Summary: 6 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Med12^tm1.1Hsch/Med12^tm1.1Hsch	involves: 129S6/SvEvTac * C57BL/6NCrl	MGI:4839515
cn2	Med12^tm1.1Hsch/Med12^+ Tg(CMV-cre)1Cgn/0	involves: 129S6/SvEvTac * C57BL/6	MGI:4839553
cn3	Med12^tm1.1Hsch/Y Tg(Myh6-cre)2182Mds/0	involves: 129S6/SvEvTac * C57BL/6NCrl * FVB/N	MGI:7378740
cn4	Med12^tm1.1Hsch/Med12^+ Tg(Myh6-cre)2182Mds/0	involves: 129S6/SvEvTac * C57BL/6NCrl * FVB/N	MGI:8448545
cn5	Med12^tm1.1Hsch/Med12^tm1.1Hsch Tg(Myh6-cre)2182Mds/0	involves: 129S6/SvEvTac * C57BL/6NCrl * FVB/N	MGI:8448547
ot6	Med12^tm1.1Hsch/Y	involves: 129S6/SvEvTac * C57BL/6NCrl	MGI:4839514

Genotype
MGI:4839515

hm1

• Allelic Composition: Med12^tm1.1Hsch/Med12^tm1.1Hsch
• Genetic Background: involves: 129S6/SvEvTac * C57BL/6NCrl

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

normal phenotype

no abnormal phenotype detected ( J:166040 )

♀ • mice are fertile with no abnormal phenotype

Genotype
MGI:4839553

cn2

• Allelic Composition: Med12^tm1.1Hsch/Med12⁺; Tg(CMV-cre)1Cgn/0
• Genetic Background: involves: 129S6/SvEvTac * C57BL/6

mortality/aging

prenatal lethality, incomplete penetrance ( J:166045 )

♀ • only one female in 16 live births

embryonic lethality during organogenesis, incomplete penetrance ( J:166045 )

♀ • fewer female embryos from a cross of hemizygous males and homozygous cre expressing females at E13.5

embryo

abnormal neural tube morphology ( J:166045 )

♀ • neural tube defects of variable severity at E11.5 in females

craniorachischisis ( J:166045 )

♀ • in 30% of E12.5 mice

nervous system

abnormal neural tube morphology ( J:166045 )

♀ • neural tube defects of variable severity at E11.5 in females

craniorachischisis ( J:166045 )

♀ • in 30% of E12.5 mice

exencephaly ( J:166045 )

♀ • exencephaly and spina bifida in 63% of mice over E12.5

skeleton

abnormal neurocranium morphology ( J:166045 )

♀ • some calvarial bones missing

abnormal vertebral spinous process morphology ( J:166045 )

♀ • splayed spina processes

absent vertebral arch ( J:166045 )

♀

limbs/digits/tail

curly tail ( J:166045 )

♀ • in 18 of 22 mice

craniofacial

abnormal neurocranium morphology ( J:166045 )

♀ • some calvarial bones missing

Genotype
MGI:7378740

cn3

• Allelic Composition: Med12^tm1.1Hsch/Y; Tg(Myh6-cre)2182Mds/0
• Genetic Background: involves: 129S6/SvEvTac * C57BL/6NCrl * FVB/N

cardiovascular system

abnormal heart morphology ( J:267377 )

♂ • protein levels of ryanodine receptor (RyR) are decreased in P7 hearts while protein levels of ATP2A2/SERCA2a which rapidly pumps Ca2+ into the sarcoplasmic reticulum (SR) are decreased in P7 hearts and in 8-week-old heart ventricles

♂ • PLN (phospholamban), an inhibitor of ATP2A2/SERCA2a, is hyperphosphorylated in hearts with no significant change in the total protein levels of PLN in P7 hearts or 8-week-old ventricles

♂ • protein levels of GJA1/CX43 are significantly decreased in P7 hearts and remain lower in 8-week-old heart ventricles

abnormal myocardial fiber morphology ( J:267377 )

♂ • protein levels of the ryanodine receptor (RyR), ATP2A2/SERCA2a, and GJA1/CX43 are significantly reduced in cardiomyocytes (CMs) isolated from 8-week-old hearts

♂ • PLN (phospholamban), an inhibitor of ATP2A2/SERCA2a, is hyperphosphorylated in isolated CMs

increased heart weight ( J:267377 )

♂ • male heart weight (HW) to tibia length (TL) is significantly increased at 5 weeks with a further increase noted at 12 weeks of age

♂ • however, male hearts appear morphologically normal at birth

decreased heart left ventricle wall thickness ( J:267377 )

♂ • male hearts exhibit early and progressive thinning of the left ventricular wall

decreased heart left ventricle posterior wall thickness ( J:267377 )

♂ • left ventricular posterior wall thickness in diastole (LVPWD) and systole (LVPWS) are decreased by P7 and continue to decline with aging

dilated heart left ventricle ( J:267377 )

♂ • male hearts exhibit early and progressive dilation of the left ventricular chamber

cardiac interstitial fibrosis ( J:267377 )

♂ • Massons trichrome staining of adult male hearts indicates an increase in interstitial cardiac fibrosis

♂ • Picrosirius red staining shows a slight increase in fibrosis at P7 that becomes significant by 12 weeks of age

♂ • however, no significant changes are detected in cardiomyocyte death and proliferation by TUNEL and Ki-67 staining, respectively, at P1 and 12 weeks of age

dilated cardiomyopathy ( J:267377 )

♂ • male mice exhibit early-onset dilated cardiomyopathy that progresses with aging

decreased cardiac muscle contractility ( J:267377 )

♂ • fractional shortening is significantly decreased as early as P7 and declines progressively with aging

abnormal heart echocardiography feature ( J:267377 )

♂ • echocardiography conducted on unanesthetized male mice reveals early-onset cardiac dysfunction, with fractional shortening and heart rate significantly reduced as early as P7 and declining with aging

♂ • left ventricular posterior wall thickness in diastole (LVPWD) and systole (LVPWS) are decreased by P7 and continue to decline with aging

♂ • left ventricular internal dimension in diastole (LVIDD) and systole (LVIDS) are increased as early as P7 and continue to increase with aging

decreased heart rate ( J:267377 )

♂ • heart rate is significantly reduced by P7 and remains significantly lower throughout adulthood, as determined at 3, 6 and 12 weeks of age

abnormal heart electrocardiography waveform feature ( J:267377 )

♂ • electrocardiography performed on anesthetized 6-week-old male mice shows a significant decrease in heart rate to the same degree as observed in the unanesthetized state

prolonged QRS complex duration ( J:267377 )

♂ • anesthetized 6-week-old male mice exhibit a prolonged QRS interval

abnormal myocardial fiber physiology ( J:267377 )

♂ • adult cardiomyocytes (CMs) isolated from 8-week-old heart ventricles show a significant increase in fractional shortening, suggesting enhanced CM contractility

abnormal myocardial fiber calcium currents ( J:267377 )

♂ • both adult CMs isolated from 8-week-old heart ventricles and neonatal CMs isolated from P1 heart ventricles show increased peak Ca2+ transient amplitudes without changing diastolic Ca2+ levels, indicating that more Ca2+ is released during each contraction-relaxation cycle

♂ • moreover, both adult and neonatal CMs show accelerated reuptake of Ca2+ into the SR, as revealed by a faster cytosolic Ca2+ transient decay rate (reduced tau) and decreased duration of the Ca2+ transient

♂ • however, total SR Ca2+ content is not altered in adult CMs

cellular

cardiac interstitial fibrosis ( J:267377 )

♂ • Massons trichrome staining of adult male hearts indicates an increase in interstitial cardiac fibrosis

♂ • Picrosirius red staining shows a slight increase in fibrosis at P7 that becomes significant by 12 weeks of age

♂ • however, no significant changes are detected in cardiomyocyte death and proliferation by TUNEL and Ki-67 staining, respectively, at P1 and 12 weeks of age

abnormal sarcomere morphology ( J:267377 )

♂ • TEM analysis of heart left ventricles shows only a few regions containing disorganized sarcomeres at 8 weeks of age

♂ • however, sarcomeric structure is identical to that in controls throughout most heart regions

homeostasis/metabolism

abnormal calcium ion homeostasis ( J:267377 )

♂ • male hearts show altered calcium-handling gene expression and protein levels; all calcium-related genes investigated are significantly regulated at P1 (prior to the onset of dilated cardiomyopathy) and remain significantly down- or upregulated in the hearts and cardiomyocytes (CMs) of adult mice

muscle

abnormal myocardial fiber morphology ( J:267377 )

♂ • protein levels of the ryanodine receptor (RyR), ATP2A2/SERCA2a, and GJA1/CX43 are significantly reduced in cardiomyocytes (CMs) isolated from 8-week-old hearts

♂ • PLN (phospholamban), an inhibitor of ATP2A2/SERCA2a, is hyperphosphorylated in isolated CMs

dilated cardiomyopathy ( J:267377 )

♂ • male mice exhibit early-onset dilated cardiomyopathy that progresses with aging

decreased cardiac muscle contractility ( J:267377 )

♂ • fractional shortening is significantly decreased as early as P7 and declines progressively with aging

abnormal myocardial fiber physiology ( J:267377 )

♂ • adult cardiomyocytes (CMs) isolated from 8-week-old heart ventricles show a significant increase in fractional shortening, suggesting enhanced CM contractility

abnormal myocardial fiber calcium currents ( J:267377 )

♂ • both adult CMs isolated from 8-week-old heart ventricles and neonatal CMs isolated from P1 heart ventricles show increased peak Ca2+ transient amplitudes without changing diastolic Ca2+ levels, indicating that more Ca2+ is released during each contraction-relaxation cycle

♂ • moreover, both adult and neonatal CMs show accelerated reuptake of Ca2+ into the SR, as revealed by a faster cytosolic Ca2+ transient decay rate (reduced tau) and decreased duration of the Ca2+ transient

♂ • however, total SR Ca2+ content is not altered in adult CMs

abnormal sarcomere morphology ( J:267377 )

♂ • TEM analysis of heart left ventricles shows only a few regions containing disorganized sarcomeres at 8 weeks of age

♂ • however, sarcomeric structure is identical to that in controls throughout most heart regions

growth/size/body

increased heart weight ( J:267377 )

♂ • male heart weight (HW) to tibia length (TL) is significantly increased at 5 weeks with a further increase noted at 12 weeks of age

♂ • however, male hearts appear morphologically normal at birth

Genotype
MGI:8448545

cn4

• Allelic Composition: Med12^tm1.1Hsch/Med12⁺; Tg(Myh6-cre)2182Mds/0
• Genetic Background: involves: 129S6/SvEvTac * C57BL/6NCrl * FVB/N

cardiovascular system

decreased cardiac muscle contractility ( J:267377 )

♀ • fractional shortening is significantly decreased at 6 weeks but not at 3 weeks of age

abnormal heart echocardiography feature ( J:267377 )

♀ • M-mode echocardiograms indicate a slight reduction in cardiac function at 6 weeks of age

muscle

decreased cardiac muscle contractility ( J:267377 )

♀ • fractional shortening is significantly decreased at 6 weeks but not at 3 weeks of age

Genotype
MGI:8448547

cn5

• Allelic Composition: Med12^tm1.1Hsch/Med12^tm1.1Hsch; Tg(Myh6-cre)2182Mds/0
• Genetic Background: involves: 129S6/SvEvTac * C57BL/6NCrl * FVB/N

cardiovascular system

decreased cardiac muscle contractility ( J:267377 )

♀ • fractional shortening is significantly decreased at both 3 and 6 weeks of age

abnormal heart echocardiography feature ( J:267377 )

♀ • M-mode echocardiograms indicate a significant reduction in cardiac function at 6 weeks of age that is nearly identical to that in Med12^tm1.1Hsch/Y Tg(Myh6-cre)2182Mds/0 males

muscle

decreased cardiac muscle contractility ( J:267377 )

♀ • fractional shortening is significantly decreased at both 3 and 6 weeks of age

Genotype
MGI:4839514

ot6

• Allelic Composition: Med12^tm1.1Hsch/Y
• Genetic Background: involves: 129S6/SvEvTac * C57BL/6NCrl

normal phenotype

no abnormal phenotype detected ( J:166040 )

♂ • mice are fertile with no abnormal phenotype