Phenotypes associated with this allele

• Allele Symbol: Dot1l^tm1.1Tche
• Allele Name: targeted mutation 1.1, Taiping Chen
• Allele ID: MGI:4459468
• Summary: 2 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Dot1l^tm1.1Tche/Dot1l^tm1.1Tche	either: (involves: C57BL/6) or (involves: 129/Sv * C57BL/6)	MGI:4459471
cn2	Dot1l^tm1Tche/Dot1l^tm1.1Tche Tg(Myhca-cre)1Abel/0	Not Specified	MGI:5424158

Genotype
MGI:4459471

hm1

• Allelic Composition: Dot1l^tm1.1Tche/Dot1l^tm1.1Tche
• Genetic Background: either: (involves: C57BL/6) or (involves: 129/Sv * C57BL/6)

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

mortality/aging

embryonic lethality during organogenesis, complete penetrance ( J:161427 )

• mice die between E9.5 and E11.5

cellular

aneuploidy ( J:161427 )

• in embryonic stem cells without any other chromosome abnormalities

increased telomere length ( J:161427 )

• embryonic stem cells exhibit telomere elongation with activation of the alternative lengthening of telomere mechanism compared with wild-type cells

abnormal cell physiology ( J:161427 )

• embryonic stem cells exhibit reduced H3K79 di- and tri-methylation compared with wild-type cells

increased embryonic tissue cell apoptosis ( J:161427 )

• of embryonic stem cells and in focal areas of the embryos

decreased cell proliferation ( J:161427 )

• of embryonic stem cells

embryo

abnormal vitelline vasculature morphology ( J:161427 )

• yolk vasculature is underdeveloped and disorganized compared to in wild-type mice

• however, yolk sac vasculature is present and contains primitive erythrocytes

increased embryonic tissue cell apoptosis ( J:161427 )

• of embryonic stem cells and in focal areas of the embryos

embryonic growth retardation ( J:161427 )

• at E8.5, 15% of mice exhibit developmental arrest unlike wild-type mice

• remaining mice exhibit developmental arrest at E9.5

decreased embryo size ( J:161427 )

• at E9.5

growth/size/body

enlarged heart ( J:161427 )

• at E9.5

embryonic growth retardation ( J:161427 )

• at E8.5, 15% of mice exhibit developmental arrest unlike wild-type mice

• remaining mice exhibit developmental arrest at E9.5

decreased embryo size ( J:161427 )

• at E9.5

limbs/digits/tail

short tail ( J:161427 )

• stunted at E9.5

cardiovascular system

abnormal vitelline vasculature morphology ( J:161427 )

• yolk vasculature is underdeveloped and disorganized compared to in wild-type mice

• however, yolk sac vasculature is present and contains primitive erythrocytes

enlarged heart ( J:161427 )

• at E9.5

Genotype
MGI:5424158

cn2

• Allelic Composition: Dot1l^tm1Tche/Dot1l^tm1.1Tche; Tg(Myhca-cre)1Abel/0
• Genetic Background: Not Specified

mortality/aging

premature death ( J:168140 )

• mice surviving the early postnatal period died by 6 mo of age

postnatal lethality, incomplete penetrance ( J:168140 )

• sudden death was observed in 50% of the mutant mice within 2 wk after birth

cardiovascular system

abnormal heart morphology ( J:168140 )

• gross changes in heart morphology (such as deviation from an elliptical shape to a more spherical one and increased heart mass) are observed

• RT-qPCR demonstrated that expression of the fetal genes Myh7, Acta1, Nppa, and Nppb is up-regulated in mutant hearts, and adult gene Myh6 is down-regulated indicating reactivation of a fetal gene expression program

enlarged heart ( J:168140 )

increased heart weight ( J:168140 )

• heart to body weight ratios are increased compared with that of littermate controls; body weight is not significantly altered between controls and mutant mice

increased heart left ventricle size ( J:168140 )

• conscious ECHOs performed on P10 pups demonstrate that mutant mice have increased left ventricular internal dimensions and volume

dilated heart ventricle ( J:168140 )

• dilation of both heart chambers

cardiac interstitial fibrosis ( J:168140 )

• reactive fibrosis, interstitial

dilated cardiomyopathy ( J:168140 )

decreased cardiac output ( J:168140 )

• analysis of cardiac output at P10 by measuring ejection fraction and fractional shortening reveals both are reduced by almost half in mutant mice when compared with those of control mice

increased fetal cardiomyocyte proliferation ( J:168140 )

• the percentage of proliferating cardiomyocyte cells (ratio of Ki-67-positive nuclei to total nuclei, multiplied by 100) is significantly increased in the mutant hearts compared with the control, which may contribute to the observed increase in heart mass

prolonged RR interval ( J:168140 )

heart block ( J:168140 )

• mutant mice display at least a first-degree heart block at the atrioventricular node, with an 80% penetration of either nonsustained ventricular tachycardia, periodic third- degree heart block, or second-degree Type II heart block

atrioventricular block ( J:168140 )

prolonged PR interval ( J:168140 )

prolonged P wave ( J:168140 )

prolonged QRS complex duration ( J:168140 )

increased cardiomyocyte apoptosis ( J:168140 )

• at P10, TUNEL staining reveals a dramatic increase in apoptotic cell death in mutant hearts compared with the control

cellular

cardiac interstitial fibrosis ( J:168140 )

• reactive fibrosis, interstitial

increased fetal cardiomyocyte proliferation ( J:168140 )

• the percentage of proliferating cardiomyocyte cells (ratio of Ki-67-positive nuclei to total nuclei, multiplied by 100) is significantly increased in the mutant hearts compared with the control, which may contribute to the observed increase in heart mass

increased cardiomyocyte apoptosis ( J:168140 )

• at P10, TUNEL staining reveals a dramatic increase in apoptotic cell death in mutant hearts compared with the control

muscle

abnormal muscle physiology ( J:168140 )

• transmission electron microscopic (TEM) analysis reveals a significant increase of vacuoles in mutant myocytes, suggesting an increase in autophagic cell death

dilated cardiomyopathy ( J:168140 )

increased fetal cardiomyocyte proliferation ( J:168140 )

• the percentage of proliferating cardiomyocyte cells (ratio of Ki-67-positive nuclei to total nuclei, multiplied by 100) is significantly increased in the mutant hearts compared with the control, which may contribute to the observed increase in heart mass

increased cardiomyocyte apoptosis ( J:168140 )

• at P10, TUNEL staining reveals a dramatic increase in apoptotic cell death in mutant hearts compared with the control

growth/size/body

enlarged heart ( J:168140 )

increased heart weight ( J:168140 )

• heart to body weight ratios are increased compared with that of littermate controls; body weight is not significantly altered between controls and mutant mice

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
dilated cardiomyopathy 1A		DOID:0110425	OMIM:115200	J:168140