Phenotypes associated with this allele

• Allele Symbol: Kras^tm4.1Bbd
• Allele Name: targeted mutation 4.1, Mariano Barbacid
• Allele ID: MGI:5649285
• Summary: 4 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Kras^tm4.1Bbd/Kras^tm4.1Bbd	129S2.129(Cg)-Kras^tm4.1Bbd	MGI:5649290
hm2	Kras^tm4.1Bbd/Kras^tm4.1Bbd	B6J.129(FVB)-Kras^tm4.1Bbd	MGI:5649292
hm3	Kras^tm4.1Bbd/Kras^tm4.1Bbd	involves: 129S1/Sv * 129S2/SvPas * 129X1/SvJ * C57BL/6J * FVB/N	MGI:5649287
ht4	Kras^tm4.1Bbd/Kras^+	involves: 129S1/Sv * 129S2/SvPas * 129X1/SvJ * C57BL/6J * FVB/N	MGI:5649288

Genotype
MGI:5649290

hm1

• Allelic Composition: Kras^tm4.1Bbd/Kras^tm4.1Bbd
• Genetic Background: 129S2.129(Cg)-Kras^tm4.1Bbd

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

mortality/aging

perinatal lethality, incomplete penetrance ( J:223433 )

• Background Sensitivity: mice exhibit increased, but not complete, perinatal lethality on the 129S2/SvPas background compared to complete lethality on the C57BL/6J background

Genotype
MGI:5649292

hm2

• Allelic Composition: Kras^tm4.1Bbd/Kras^tm4.1Bbd
• Genetic Background: B6J.129(FVB)-Kras^tm4.1Bbd

mortality/aging

perinatal lethality, complete penetrance ( J:223433 )

• Background Sensitivity: complete perinatal lethality on the C57BL/6J background compared to partial perinatal lethality on the 129S2/SvPas background

Genotype
MGI:5649287

hm3

• Allelic Composition: Kras^tm4.1Bbd/Kras^tm4.1Bbd
• Genetic Background: involves: 129S1/Sv * 129S2/SvPas * 129X1/SvJ * C57BL/6J * FVB/N

mortality/aging

premature death ( J:223433 )

• reduced lifespan, with an average half-life of 36 weeks

perinatal lethality, incomplete penetrance ( J:223433 )

• perinatal lethality in some mutants, probably due to heart insufficiency and hematopoietic defects

• pregnant females treated with the MEK inhibitor PD0325901 from E7.5 to P9 and then direct treatment of mutant pups until P21 completely rescues perinatal lethality and heart defects observed in P0 pups, as well as the craniofacial dysmorphia and growth defects, however beginning MEK inhibitor treatment at P21 does not ameliorate the developmental defects

• median survival of mutants treated with the MEK inhibitor PD0325901 is 30% longer than vehicle treated mutants

growth/size/body

heart hyperplasia ( J:223433 )

• cardiac hyperplasia is already evident at E13.5

• increase in heart/body weight ratio characterizes the cardiac hyperplasia at 4 months of age

abnormal facial morphology ( J:223433 )

• facial dysmorphia

triangular face ( J:223433 )

• pronounced triangular facial appearance with a shorter distance between the ears and the nose, blunter snout, and wider separation between the eyes

flattened snout ( J:223433 )

• blunter snout

abnormal ear position ( J:223433 )

• shorter distance between the ears and the nose

decreased body size ( J:223433 )

• surviving mice are smaller at weaning but have normal weight at birth

slow postnatal weight gain ( J:223433 )

• surviving mice are smaller at weaning but have normal weight at birth

• at 4 weeks of age, males weigh only 72% of wild-type mice, however this difference is ameliorated by 3 months of age

decreased body length ( J:223433 )

• at 4 weeks of age, males are 23% shorter than wild-type mice, however this difference is ameliorated by 3 months of age

enlarged spleen ( J:223433 )

• severe splenomegaly at 4 months of age

craniofacial

abnormal cranium morphology ( J:223433 )

• increase in skull width and height along with reduction in length results in a rounder skull with bigger volume

decreased cranium length ( J:223433 )

• at 4 months of age

increased cranium height ( J:223433 )

• at 4 months of age

increased cranium width ( J:223433 )

• at 4 months of age

abnormal facial morphology ( J:223433 )

• facial dysmorphia

triangular face ( J:223433 )

• pronounced triangular facial appearance with a shorter distance between the ears and the nose, blunter snout, and wider separation between the eyes

flattened snout ( J:223433 )

• blunter snout

abnormal ear position ( J:223433 )

• shorter distance between the ears and the nose

hearing/vestibular/ear

abnormal ear position ( J:223433 )

• shorter distance between the ears and the nose

hematopoietic system

abnormal hematopoietic system morphology/development ( J:223433 )

• mice develop a myeloproliferative disorder and exhibit lymphoid and myeloid infiltrates in a variety of organs, including liver, kidney, and lung

• treatment with the MEK inhibitor PD0325901 slows down progression but does not prevent myeloproliferative disease

spleen vascular congestion ( J:223433 )

• splenomegaly is due to congestion and increased extramedullary hematopoiesis

enlarged spleen ( J:223433 )

• severe splenomegaly at 4 months of age

abnormal common myeloid progenitor cell morphology ( J:223433 )

• increase in numbers of common myeloid progenitors (Lin-/IL7Ralpha-/Sca-1-/c-Kit+/FcgammaRlow/CD34+)

extramedullary hematopoiesis ( J:223433 )

• splenomegaly is due to congestion and increased extramedullary hematopoiesis

anemia ( J:223433 )

increased granulocyte monocyte progenitor cell number ( J:223433 )

• increase in numbers of granulocyte-macrophage progenitors (Lin-/IL7Ralpha-/Sca-1-/c-Kit+/FcgammaRhigh/CD34+)

• however, numbers of megakaryocyte-erythroid progenitors seem normal

abnormal common lymphocyte progenitor cell morphology ( J:223433 )

• slight increase in numbers of common lymphoid progenitors (Lin-/IL7Ralpha+/Sca-1low/c-Kitlow)

thrombocytopenia ( J:223433 )

decreased CD8-positive, alpha-beta T cell number ( J:223433 )

• decrease in the percentage of CD8+ T cells

increased leukocyte cell number ( J:223433 )

• increase in the number of leukocytes in peripheral blood , mainly due to expansion of neutrophils, eosinophils, and basophils

increased basophil cell number ( J:223433 )

increased eosinophil cell number ( J:223433 )

increased neutrophil cell number ( J:223433 )

increased myeloid cell number ( J:223433 )

• expansion of myeloid cells in the spleen, with increased levels of both Gr1+/CD11b+ and CD11b+ cells

increased hematopoietic stem cell number ( J:223433 )

• mice exhibit an increase in LSK (Lin-/Sca-1+/c-Kit+) cells in the bone marrow

abnormal bone marrow cell physiology ( J:223433 )

• bone marrow cells proliferate in the absence of cytokines unlike wild-type cells and proliferate more robustly than control bone marrow cells in the presence of cytokines

cardiovascular system

spleen vascular congestion ( J:223433 )

• splenomegaly is due to congestion and increased extramedullary hematopoiesis

abnormal heart morphology ( J:223433 )

• thickening of all chambers

• expansion of Sca-1+/PDGFRalpha+/CD31- cardiac stem cells from hearts of unweaned (P10-P14) mice

• however, mice do not display hypertension, heart fibrosis or cardiovascular remodeling

increased myocardial fiber number ( J:223433 )

• increased size of heart is due to an increase in numbers of cardiomyocytes and not by increased cell size

heart hyperplasia ( J:223433 )

• cardiac hyperplasia is already evident at E13.5

• increase in heart/body weight ratio characterizes the cardiac hyperplasia at 4 months of age

thick aortic valve ( J:223433 )

increased cardiac output ( J:223433 )

• cardiac output is increased in 4 month old mice

increased cardiac muscle contractility ( J:223433 )

• fractional shortening is increased in 4 month old mice

• 4 month old mice show increased wall thickness in systole, systolic wall thickening, and left ventricle mass, and increased end diastolic volume, however end systolic volume is normal and no differences in the wall thickness in diastole, ejection fraction, or heart rate indicating normal heart function

abnormal myocardial fiber physiology ( J:223433 )

• higher proliferation rate in cardiomyocytes of 4 month old mice

cellular

cellular necrosis ( J:223433 )

• mice that die at P0 show focal necrosis in tissues ilike the liver and muscle

increased cell proliferation ( J:223433 )

• MEFs show higher growth rate than wild-type MEFs when grown in culture

immune system

spleen vascular congestion ( J:223433 )

• splenomegaly is due to congestion and increased extramedullary hematopoiesis

enlarged spleen ( J:223433 )

• severe splenomegaly at 4 months of age

decreased CD8-positive, alpha-beta T cell number ( J:223433 )

• decrease in the percentage of CD8+ T cells

increased leukocyte cell number ( J:223433 )

• increase in the number of leukocytes in peripheral blood , mainly due to expansion of neutrophils, eosinophils, and basophils

increased basophil cell number ( J:223433 )

increased eosinophil cell number ( J:223433 )

increased neutrophil cell number ( J:223433 )

muscle

increased myocardial fiber number ( J:223433 )

• increased size of heart is due to an increase in numbers of cardiomyocytes and not by increased cell size

increased cardiac muscle contractility ( J:223433 )

• fractional shortening is increased in 4 month old mice

• 4 month old mice show increased wall thickness in systole, systolic wall thickening, and left ventricle mass, and increased end diastolic volume, however end systolic volume is normal and no differences in the wall thickness in diastole, ejection fraction, or heart rate indicating normal heart function

renal/urinary system

abnormal kidney morphology ( J:223433 )

• kidneys frequently show infiltration from hematopoietic cells

• however, no abnormalities are seen in renal morphology or histology

skeleton

abnormal cranium morphology ( J:223433 )

• increase in skull width and height along with reduction in length results in a rounder skull with bigger volume

decreased cranium length ( J:223433 )

• at 4 months of age

increased cranium height ( J:223433 )

• at 4 months of age

increased cranium width ( J:223433 )

• at 4 months of age

vision/eye

ocular hypertelorism ( J:223433 )

• wider separation between the eyes

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Noonan syndrome 3		DOID:0060581	OMIM:609942	J:223433

Genotype
MGI:5649288

ht4

• Allelic Composition: Kras^tm4.1Bbd/Kras⁺
• Genetic Background: involves: 129S1/Sv * 129S2/SvPas * 129X1/SvJ * C57BL/6J * FVB/N

mortality/aging

premature death ( J:223433 )

• mice exhibit a reduced life span, with an average half-life of 62 weeks

hematopoietic system

enlarged spleen ( J:223433 )

immune system

enlarged spleen ( J:223433 )

growth/size/body

enlarged spleen ( J:223433 )