Phenotypes associated with this allele

• Allele Symbol: Braf^tm1Tumg
• Allele Name: targeted mutation 1, Yoko Aoki
• Allele ID: MGI:5902220
• Summary: 4 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
cn1	Braf^tm1Tumg/Braf^+ Tg(CAG-cre)2Osb/0	involves: BALB/c * C57BL * C57BL/6J * DBA	MGI:6164158
cn2	Braf^tm1Tumg/Braf^+ Tg(CAG-cre)2Osb/0	involves: C57BL * C57BL/6J * DBA	MGI:5902221
cn3	Braf^tm1Tumg/Braf^tm1Tumg Tg(CAG-cre)2Osb/0	involves: C57BL * C57BL/6J * DBA * ICR	MGI:6164160
cn4	Braf^tm1Tumg/Braf^+ Tg(CAG-cre)2Osb/0	involves: C57BL * C57BL/6J * DBA * ICR	MGI:6164161

Genotype
MGI:6164158

cn1

• Allelic Composition: Braf^tm1Tumg/Braf⁺; Tg(CAG-cre)2Osb/0
• Genetic Background: involves: BALB/c * C57BL * C57BL/6J * DBA

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

mortality/aging

premature death ( J:226977 )

• a few mice survive to adulthood, although all mice die within 24 weeks

postnatal lethality, incomplete penetrance ( J:226977 )

• about 50% of mice die at P5 and 90% at weaning (P28)

growth/size/body

enlarged heart ( J:226977 )

• mice exhibit higher heart weight to body weight ratio at P5, indicating cardiomegaly

postnatal growth retardation ( J:226977 )

cardiovascular system

ostium secundum atrial septal defect ( J:226977 )

• 5 of 6 mice exhibit a large secundum atrial septal defect (ASDII), while 1 of 6 mice exhibit a small ASDII or patent foramen ovale

• however, cardiac valve defects and apparent abnormalities in other tissues are not seen

patent cardiac foramen ovale ( J:226977 )

• 1 of 6 mice exhibit a small ASDII or patent foramen ovale

enlarged heart ( J:226977 )

• mice exhibit higher heart weight to body weight ratio at P5, indicating cardiomegaly

integument

sparse hair ( J:226977 )

ruffled hair ( J:226977 )

liver/biliary system

hepatic necrosis ( J:226977 )

• 36% of mice show liver necrosis at P3

reproductive system

female infertility ( J:226977 )

♀ • females are infertile

♀ • however, males are fertile

Genotype
MGI:5902221

cn2

• Allelic Composition: Braf^tm1Tumg/Braf⁺; Tg(CAG-cre)2Osb/0
• Genetic Background: involves: C57BL * C57BL/6J * DBA

cardiovascular system

abnormal heart morphology ( J:216228 )

• 93% of hearts at E16.5 show various defects

abnormal coronary artery morphology ( J:216228 )

• 3 of 14 embryos show hypoplasia of the coronary arteries

abnormal myocardial trabeculae morphology ( J:216228 )

• E14.5 hearts show an increase in density of trabeculae (hypertrabeculation)

• 4 of 14 embryos exhibit a thickened trabecular layer and thinned compact layer in the left, right, or combined myocardium

thin myocardium compact layer ( J:216228 )

• 4 of 14 embryos exhibit a thickened trabecular layer and thinned compact layer in the left, right, or combined myocardium

abnormal heart development ( J:216228 )

• hearts exhibit enhanced cell proliferation

• at E13.5, the interventricular septum and myocardium show enhanced cell proliferation

• at E16.5, the pulmonary valves and the interventricular septum in fetuses with ventricular septal defect, show enhanced cell proliferation

abnormal atrioventricular cushion morphology ( J:216228 )

• 2 of 14 embryos exhibit abnormal endocardial cushion

mitral valve hypertrophy ( J:216228 )

• 9 of 14 embryos show hypertrophy of mitral valves

• co-treatment with PD0325901 and an inhibitor of histone H3K27 demethylase UTX, GSK-J4, ameliorates enlarged mitral valves, however, no difference in the frequency of heart defects is seen

tricuspid valve hypertrophy ( J:216228 )

• 8 of 14 embryos show hypertrophy of tricuspid valves

• co-treatment with PD0325901 and an inhibitor of histone H3K27 demethylase UTX, GSK-J4, ameliorates enlarged tricuspid valves, however, no difference in the frequency of heart defects is seen

thick tricuspid valve ( J:216228 )

• ventricular radius and the thickness of the tricuspid valves are higher

ventricular septal defect ( J:216228 )

• 2 of 14 embryos exhibit ventricular septal defect

enlarged heart ( J:216228 )

• increase in heart size at E16.5

abnormal pulmonary valve cusp morphology ( J:216228 )

• hypertrophy in pulmonary valve leaflets is prominent, plugging the entire space of the pulmonary valve ring

enlarged pulmonary valve ( J:216228 )

• E12.5 hearts show an enlarged pulmonary valve

• co-treatment with PD0325901 and an inhibitor of histone H3K27 demethylase UTX, GSK-J4, ameliorates enlarged pulmonary valves, however, no difference in the frequency of heart defects is seen

pulmonary valve hypertrophy ( J:216228 )

• 7 of 14 embryos show hypertrophy of pulmonary valves

thick pulmonary valve ( J:216228 )

• ventricular radius and the thickness of the pulmonary valves are higher

abnormal epicardium morphology ( J:216228 )

• 2 of 14 embryos show epicardial blisters

hemorrhage ( J:216228 )

• at E16.5, about 9.8% of embryos are hemorrhagic and edematous

pulmonary alveolar hemorrhage ( J:216228 )

• about 11.1% of fetuses at E18.5 and E19.5 show alveolar hemorrhage

• however, lungs are able to inflate

immune system

abnormal lymph organ development ( J:216228 )

• cavities such as the jugular lymphatic sacs from E12.5 to E14.5 are observed unlike in wild-type where they are hardly observed at this time, suggesting defective lymphatic development from the cardinal vein

• marker analysis indicates that embryos show defective lymphatic development from the cardinal vein, leading to distended and blood-filled jugular lymphatic sacs at E12.5 and E16.5, dilated lymphatic vessels and edema

craniofacial

mandible hypoplasia ( J:216228 )

• 5.1% of embryos show mandibular hypoplasia and kyphosis

homeostasis/metabolism

cyanosis ( J:216228 )

• embryos delivered by cesarean section at E18.5 and E19.5 are pale, without movement and gasp for breath with cyanotic appearance and death within a few hours

edema ( J:216228 )

• at E16.5, about 9.8% of embryos are hemorrhagic and edematous

liver/biliary system

small liver ( J:216228 )

decreased liver weight ( J:216228 )

• decrease in liver weight is seen already at E16.5

hepatic necrosis ( J:216228 )

• 88% of E18.5 fetuses show severe peripheral liver necrosis with decreased liver size and liver weight

mortality/aging

neonatal lethality, complete penetrance ( J:216228 )

• no surviving mice are seen at weaning and survival rate of embryos drops after E16.5 indicating embryonic and neonatal lethality

lethality throughout fetal growth and development, incomplete penetrance ( J:216228 )

• no surviving mice are seen at weaning and survival rate of embryos drops after E16.5 indicating embryonic and neonatal lethality

• treatment of pregnant mice with the MEK inhibitor PD0325901 partly rescues embryonic lethality and combined treatment with PD0325901 and a histone demethylase inhibitor further increases survival rate

muscle

abnormal myocardial trabeculae morphology ( J:216228 )

• E14.5 hearts show an increase in density of trabeculae (hypertrabeculation)

• 4 of 14 embryos exhibit a thickened trabecular layer and thinned compact layer in the left, right, or combined myocardium

thin myocardium compact layer ( J:216228 )

• 4 of 14 embryos exhibit a thickened trabecular layer and thinned compact layer in the left, right, or combined myocardium

respiratory system

pulmonary alveolar hemorrhage ( J:216228 )

• about 11.1% of fetuses at E18.5 and E19.5 show alveolar hemorrhage

• however, lungs are able to inflate

skeleton

mandible hypoplasia ( J:216228 )

• 5.1% of embryos show mandibular hypoplasia and kyphosis

kyphosis ( J:216228 )

• 5.1% of embryos show mandibular hypoplasia and kyphosis

growth/size/body

enlarged heart ( J:216228 )

• increase in heart size at E16.5

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
cardiofaciocutaneous syndrome		DOID:0060233	OMIM:PS115150	J:216228

Genotype
MGI:6164160

cn3

• Allelic Composition: Braf^tm1Tumg/Braf^tm1Tumg; Tg(CAG-cre)2Osb/0
• Genetic Background: involves: C57BL * C57BL/6J * DBA * ICR

mortality/aging

postnatal lethality, complete penetrance ( J:226977 )

• all mice die within 19 days of birth

Genotype
MGI:6164161

cn4

• Allelic Composition: Braf^tm1Tumg/Braf⁺; Tg(CAG-cre)2Osb/0
• Genetic Background: involves: C57BL * C57BL/6J * DBA * ICR

mortality/aging

postnatal lethality, incomplete penetrance ( J:226977 )

• about 50% of mice survive for over 4 weeks, while 31% survive for over 74 weeks

growth/size/body

increased heart weight ( J:226977 )

• heart weight to body weight ratio is higher

• however heart size at 26 weeks of age is normal, no differences in cardiomyocyte size or number and no fibrosis is seen

round head ( J:226977 )

ovary cyst ( J:226977 )

♀ • 67% of females develop a unilateral ovarian cyst filled with serous fluid at 10 weeks of age

♀ • at 26 weeks of age, 100% of females have unilateral or bilateral severe ovarian cysts

slow postnatal weight gain ( J:226977 )

• although body weights of mice are normal from birth to 2 days, after 1 week, weights are lower

cardiovascular system

abnormal myocardial fiber morphology ( J:226977 )

• cardiomyocytes from 2 of 4 mice exhibit irregularly shaped and heterogeneous size of mitochondria, while the other half of remaining mice have numerous granules in the mitochondria, indicating cell injury

• however, cardiomyocytes exhibit normal sarcomeric structure and sarcoplasmic reticulum

abnormal myocardial trabeculae morphology ( J:226977 )

• 4 of 7 E16.5 mutants have a dramatic increase in the density of trabeculae

thick mitral valve cusps ( J:226977 )

• thickened at E16.5

atrial septal defect ( J:226977 )

• echocardiography shows blood flow from the left atrium to right atrium in 3 of 7 adult mice, indicating presence of atrial septal defects

increased heart weight ( J:226977 )

• heart weight to body weight ratio is higher

• however heart size at 26 weeks of age is normal, no differences in cardiomyocyte size or number and no fibrosis is seen

thick pulmonary valve cusps ( J:226977 )

• 4 of 7 E16.5 mutants show thickened pulmonary valve leaflets

pulmonary valve stenosis ( J:226977 )

• pulsed-wave Doppler waveforms at the pulmonary valve show higher ejection speed, indicating pulmonary stenosis in adults

• pulmonary valve stenosis is induced by thickened valve leaflets without evidence of infundibular stenosis

• however, M-mode echocardiography shows normal systolic and diastolic function in adults

craniofacial

decreased cranium length ( J:226977 )

• skull lengths are shorter in 8 week old mice

• however, skull widths are normal

round head ( J:226977 )

behavior/neurological

impaired contextual conditioning behavior ( J:226977 )

• in the contextual fear-conditioning test, mice show reduced freezing behavior in response to re-presentation of the context, indicating a learning deficit

decreased food intake ( J:226977 )

• stomach milk contents are decreased in all mice, suggesting a feeding problem

abnormal locomotor behavior ( J:226977 )

• slight decrease in the moving speed in the open-field test and in the Y-maze test

• however, overall behavior of the mice is essentially normal in the open-field, light-dark transition test, and Y-maze

decreased vertical activity ( J:226977 )

• slight decrease in the total rearing number in the open-field test

endocrine/exocrine glands

ovary cyst ( J:226977 )

♀ • 67% of females develop a unilateral ovarian cyst filled with serous fluid at 10 weeks of age

♀ • at 26 weeks of age, 100% of females have unilateral or bilateral severe ovarian cysts

integument

sparse hair ( J:226977 )

ruffled hair ( J:226977 )

long nails ( J:226977 )

• 68% of mice exhibit long and/or dystrophic nails

nail dystrophy ( J:226977 )

• 68% of mice exhibit long and/or dystrophic nails

limbs/digits/tail

polydactyly ( J:226977 )

• 50% of mice exhibit extra digits on the forelimbs, while 3.6% of mice exhibit extra digits on the hindlimbs

muscle

abnormal myocardial fiber morphology ( J:226977 )

• cardiomyocytes from 2 of 4 mice exhibit irregularly shaped and heterogeneous size of mitochondria, while the other half of remaining mice have numerous granules in the mitochondria, indicating cell injury

• however, cardiomyocytes exhibit normal sarcomeric structure and sarcoplasmic reticulum

abnormal myocardial trabeculae morphology ( J:226977 )

• 4 of 7 E16.5 mutants have a dramatic increase in the density of trabeculae

reproductive system

ovary cyst ( J:226977 )

♀ • 67% of females develop a unilateral ovarian cyst filled with serous fluid at 10 weeks of age

♀ • at 26 weeks of age, 100% of females have unilateral or bilateral severe ovarian cysts

female infertility ( J:226977 )

♀ • 50% of females are infertile

skeleton

decreased cranium length ( J:226977 )

• skull lengths are shorter in 8 week old mice

• however, skull widths are normal

kyphosis ( J:226977 )

• some mice have hunched appearance such as kyphosis

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
cardiofaciocutaneous syndrome		DOID:0060233	OMIM:PS115150	J:226977