Phenotypes associated with this allele

• Allele Symbol: Ptpn11⁺
• Allele Name: wild type
• Allele ID: MGI:2176528
• Summary: 26 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
ht1	Ptpn11^tm1Bgn/Ptpn11^+	129S6.129S4-Ptpn11^tm1Bgn	MGI:3840263
ht2	Ptpn11^tm1Bgn/Ptpn11^+	B6.129S4-Ptpn11^tm1Bgn	MGI:3840262
ht3	Ptpn11^tm4.2Bgn/Ptpn11^+	B6.129S6-Ptpn11^tm4.2Bgn	MGI:6507961
ht4	Ptpn11^tm1Bgn/Ptpn11^+	C.129S4-Ptpn11^tm1Bgn	MGI:3840261
ht5	Ptpn11^tm1Rbn/Ptpn11^+	involves: 129 * Black Swiss	MGI:2176529
ht6	Ptpn11^tm1.1Ics/Ptpn11^+	involves: 129S2/SvPas * C57BL/6 * FVB/N	MGI:5639083
ht7	Ptpn11^tm7Bgn/Ptpn11^+	involves: 129S4/SvJae * 129S6/SvEvTac * C57BL/6	MGI:3840258
ht8	Ptpn11^tm1Bgn/Ptpn11^+	involves: 129S4/SvJae * C57BL/6	MGI:3840260
ht9	Ptpn11^tm1Bgn/Ptpn11^+	involves: 129S4/SvJae * C57BL/6J	MGI:3050469
ht10	Ptpn11^tm1Ckq/Ptpn11^+	involves: 129S6/SvEvTac * C57BL/6J	MGI:5295463
ht11	Ptpn11^tm4.2Bgn/Ptpn11^+	involves: 129S6/SvEvTac * C57BL/6J * FVB/N	MGI:5004709
cn12	Emx1^tm1(cre)Krj/Emx1^+ Ptpn11^tm6Bgn/Ptpn11^+	B6.129S-Ptpn11^tm6Bgn Emx1^tm1(cre)Krj	MGI:6095197
cn13	Cd19^tm1(cre)Cgn/Cd19^+ Ptpn11^tm1Ckq/Ptpn11^+	involves: 129P2/OlaHsd * 129S6/SvEvTac * C57BL/6J	MGI:5295466
cn14	Ptpn11^tm1Ckq/Ptpn11^+ Lyz2^tm1(cre)Ifo/Lyz2^+	involves: 129P2/OlaHsd * 129S6/SvEvTac * C57BL/6J	MGI:5295468
cn15	Hprt1^tm1(CAG-cre)Mnn/Hprt1^+ Ptpn11^tm1Ckq/Ptpn11^+	involves: 129S1/Sv * 129S6/SvEvTac * C57BL/6J	MGI:5295464
cn16	Meox2^tm1(cre)Sor/Meox2^+ Ptpn11^tm6Bgn/Ptpn11^+	involves: 129S4/SvJaeSor * 129S6/SvEvTac * C57BL/6	MGI:3840253
cn17	Ptpn11^tm6Bgn/Ptpn11^+ Tg(Tek-cre)12Flv/0	involves: 129S6/SvEvTac * C3H * C57BL/6	MGI:3840254
cn18	Ptpn11^tm1Ckq/Ptpn11^+ Tg(Mx1-cre)1Cgn/0	involves: 129S6/SvEvTac * C57BL/6 * C57BL/6J * CBA	MGI:5295465
cn19	Ptpn11^tm6Bgn/Ptpn11^+ Tg(CAG-cre/Esr1*)5Amc/0	involves: 129S6/SvEvTac * C57BL/6 * CBA	MGI:3845013
cn20	Ptpn11^tm6Bgn/Ptpn11^+ Tg(Mx1-cre)1Cgn/0	involves: 129S6/SvEvTac * C57BL/6 * CBA	MGI:3845014
cn21	Ptpn11^tm6Bgn/Ptpn11^+ H2az2^Tg(Wnt1-cre)11Rth/H2az2^+	involves: 129S6/SvEvTac * C57BL/6 * CBA/J	MGI:3840256
cn22	Ptpn11^tm6Bgn/Ptpn11^+ Tg(Myh6-cre)2182Mds/0	involves: 129S6/SvEvTac * C57BL/6 * FVB/N	MGI:3840255
cn23	Ptpn11^tm1Ckq/Ptpn11^+ Tg(Lck-cre)1Cwi/0	involves: 129S6/SvEvTac * C57BL/6J	MGI:5295469
cn24	Ptpn11^tm6Bgn/Ptpn11^+ Tg(EIIa-cre)C5379Lmgd/0	involves: 129S6/SvEvTac * FVB/N	MGI:3845015
cx25	Egfr^wa2/Egfr^wa2 Ptpn11^tm1Rbn/Ptpn11^+	involves: 129 * B6EiC3Sn-a/A-Egfr^wa2 Wnt3a^vt	MGI:2176546
cx26	Egfr^wa2/Egfr^wa2 Ptpn11^tm1Paw/Ptpn11^+	involves: 129S1/Sv * 129X1/SvJ * B6EiC3Sn a/A-Egfr^wa2 Wnt3a^vt * C57BL/6	MGI:2176569

Genotype
MGI:3840263

ht1

• Allelic Composition: Ptpn11^tm1Bgn/Ptpn11⁺
• Genetic Background: 129S6.129S4-Ptpn11^tm1Bgn

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

mortality/aging

mortality/aging ( J:147154 )

N • Background Sensitivity: unlike mice on a congenic C57BL/6 background nearly all mice survive

Genotype
MGI:3840262

ht2

• Allelic Composition: Ptpn11^tm1Bgn/Ptpn11⁺
• Genetic Background: B6.129S4-Ptpn11^tm1Bgn

mortality/aging

perinatal lethality, incomplete penetrance ( J:147154 )

• Background Sensitivity: penetrance of lethality is increased compared to mice on a 129S6/SvEv or BALB/c congenic background and to mice on a mixed 129S4/SvJae and C57BL/6 background

• almost all mice die

cardiovascular system

abnormal heart morphology ( J:147154 )

• all mice show severe cardiac defects

Genotype
MGI:6507961

ht3

• Allelic Composition: Ptpn11^tm4.2Bgn/Ptpn11⁺
• Genetic Background: B6.129S6-Ptpn11^tm4.2Bgn

cardiovascular system

abnormal interventricular septum morphology ( J:301775 )

• increased interventricular septum wall (IVS) thickness

increased heart weight ( J:301775 )

• increased heart weight and HW to body weight ratio at age 16 weeks

thick ventricular wall ( J:301775 )

• increased left ventricular posterior wall (LVPW) thickness at age 16 weeks

cardiac fibrosis ( J:301775 )

growth/size/body

increased heart weight ( J:301775 )

• increased heart weight and HW to body weight ratio at age 16 weeks

Genotype
MGI:3840261

ht4

• Allelic Composition: Ptpn11^tm1Bgn/Ptpn11⁺
• Genetic Background: C.129S4-Ptpn11^tm1Bgn

mortality/aging

perinatal lethality, incomplete penetrance ( J:147154 )

• about 50% of mice die either in late gestation or perinatally

• Background Sensitivity: penetrance of lethality is decreased compared to mice on a congenic C57BL/6 background

Genotype
MGI:2176529

ht5

• Allelic Composition: Ptpn11^tm1Rbn/Ptpn11⁺
• Genetic Background: involves: 129 * Black Swiss

normal phenotype

no abnormal phenotype detected ( J:35137 )

• heterozygotes show no significant differences in body weight, plasma insulin, glucose levels during fasting or after a glucose challenge, insulin-stimulated glucose uptake in soleus muscle and adipocytes, and insulin-inhibited lipolysis in adipocytes relative to wild-type mice

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
NOT	Noonan syndrome 1	DOID:0060578	OMIM:163950	J:35137

Genotype
MGI:5639083

ht6

• Allelic Composition: Ptpn11^tm1.1Ics/Ptpn11⁺
• Genetic Background: involves: 129S2/SvPas * C57BL/6 * FVB/N

adipose tissue

decreased brown adipose tissue amount ( J:216593 )

• brown adipose tissue is smaller

decreased subcutaneous adipose tissue amount ( J:216593 )

• subcutaneous white adipose tissues are smaller

decreased total body fat amount ( J:216593 )

• fat mass is decreased, showing on average 2/3 less fat mass than wild-type mice

• epididymal, subcutaneous, and perirenal white adipose tissues are smaller

abnormal fat cell differentiation ( J:216593 )

• preadipocytes show impaired differentiation into adipocytes in culture

decreased white fat cell number ( J:216593 )

• adipocyte number is reduced by about half in epididymal fat pads

increased fat cell size ( J:216593 )

• mean diameter is increased in adipocytes of epididymal fat pads and there is a depletion of the small adipocyte subpopulation

• increase in proportion of larger adipocytes in subcutaneous adipose tissue

abnormal epididymal fat pad morphology ( J:216593 )

• epididymal adipose tissues are smaller

increased adipocyte glucose uptake ( J:216593 )

• insulin-induced glucose uptake is increased in isolated adipocytes from epididymal tissue

cardiovascular system

abnormal heart septum morphology ( J:216593 )

• thinning of the intraventricular septum

enlarged heart ( J:216593 )

• increase in heart/body ratio in 30 week old mice

cardiac hypertrophy ( J:216593 )

• mice develop hypertrophic cardiomyopathy that evolves to dilated cardiomyopathy

heart left ventricle hypertrophy ( J:216593 )

• 15 week old mice show enlargement of the left ventricle, showing early stage of hypertrophy

decreased heart left ventricle posterior wall thickness ( J:216593 )

• thinning of the left ventricular posterior wall

dilated heart left ventricle ( J:216593 )

• increase in left ventricular internal diameter

dilated cardiomyopathy ( J:216593 )

decreased cardiac stroke volume ( J:216593 )

decreased cardiac muscle contractility ( J:216593 )

• hearts exhibit cardiac dysfunction as indicated by reduced stroke volume and proportional decrease in fractional shortening and ejection fraction

decreased heart rate ( J:216593 )

• decrease in pulse height and heart rate

decreased systemic arterial blood pressure ( J:216593 )

craniofacial

abnormal cranium size ( J:216593 )

• increase in skull width-to-length ratio

decreased cranium length ( J:216593 )

growth/size/body

enlarged heart ( J:216593 )

• increase in heart/body ratio in 30 week old mice

cardiac hypertrophy ( J:216593 )

• mice develop hypertrophic cardiomyopathy that evolves to dilated cardiomyopathy

heart left ventricle hypertrophy ( J:216593 )

• 15 week old mice show enlargement of the left ventricle, showing early stage of hypertrophy

increased lean body mass ( J:216593 )

• lean mass proportion is increased

decreased susceptibility to diet-induced obesity ( J:216593 )

• mice are resistant to high-fat diet induced obesity, gaining less weight, showing a reduction in fat mass, smaller adipose tissue deposits, lower amount of small adipocytes and more big adipocytes, lower plasma leptin levels, lower glycaemia, reduced insulin levels, a decrease in insulin resistance, improved insulin tolerance, lower cholesterol in plasma, reduction in lipid deposits in the liver and muscle, and lower hepatic triglyceride levels

postnatal growth retardation ( J:216593 )

• slight growth and weight retardation

slow postnatal weight gain ( J:216593 )

• mice gain less weight than wild-type littermates (16% less at 26 weeks of age) despite similar food intake

• chronic treatment with the MEK inhibitor PD0325901, but not rapamycin, results in weight and adiposity gain

enlarged spleen ( J:216593 )

hematopoietic system

enlarged spleen ( J:216593 )

immune system

enlarged spleen ( J:216593 )

muscle

heart left ventricle hypertrophy ( J:216593 )

• 15 week old mice show enlargement of the left ventricle, showing early stage of hypertrophy

dilated cardiomyopathy ( J:216593 )

decreased cardiac muscle contractility ( J:216593 )

• hearts exhibit cardiac dysfunction as indicated by reduced stroke volume and proportional decrease in fractional shortening and ejection fraction

decreased skeletal muscle triglyceride level ( J:216593 )

• in the gastrocnemius muscle

skeleton

abnormal cranium size ( J:216593 )

• increase in skull width-to-length ratio

decreased cranium length ( J:216593 )

vision/eye

ocular hypertelorism ( J:216593 )

• increase in interorbital distance

cellular

abnormal fat cell differentiation ( J:216593 )

• preadipocytes show impaired differentiation into adipocytes in culture

increased adipocyte glucose uptake ( J:216593 )

• insulin-induced glucose uptake is increased in isolated adipocytes from epididymal tissue

homeostasis/metabolism

decreased circulating glucose level ( J:216593 )

• on both a normal diet and high-fat diet

decreased circulating insulin level ( J:216593 )

• on both a normal diet and high-fat diet

decreased circulating leptin level ( J:216593 )

• leptinemia is more than 4-fold reduced

decreased circulating alanine transaminase level ( J:216593 )

increased energy expenditure ( J:216593 )

• mice exhibit enhanced energy expenditure at the whole body level, both under normal diet and high-fat diet

• however, food intake is normal, feces contain similar amounts of energy as wild-type feces, indicating normal intestinal absorption, body temperature is normal, and mice show normal locomotor activity and respiratory quotient

decreased susceptibility to diet-induced obesity ( J:216593 )

• mice are resistant to high-fat diet induced obesity, gaining less weight, showing a reduction in fat mass, smaller adipose tissue deposits, lower amount of small adipocytes and more big adipocytes, lower plasma leptin levels, lower glycaemia, reduced insulin levels, a decrease in insulin resistance, improved insulin tolerance, lower cholesterol in plasma, reduction in lipid deposits in the liver and muscle, and lower hepatic triglyceride levels

improved glucose tolerance ( J:216593 )

• mice exhibit improved glucose tolerance in the oral glucose tolerance test

increased insulin sensitivity ( J:216593 )

• mice exhibit improved insulin tolerance

• the dose of insulin necessary to induce glucose transport and to reach a plateau are lower in adipocytes, suggesting increased insulin sensitivity

decreased circulating adiponectin level ( J:216593 )

abnormal lipid level ( J:216593 )

• lipid deposits in liver and muscle are decreased

increased glycerol level ( J:216593 )

• basal glycerol release is increased in epididymal fat pad adipocytes, indicating enhanced lipolysis

decreased liver triglyceride level ( J:216593 )

decreased skeletal muscle triglyceride level ( J:216593 )

• in the gastrocnemius muscle

abnormal carbohydrate metabolism ( J:216593 )

• mice exhibit improved carbohydrate metabolism

enhanced lipolysis ( J:216593 )

• basal glycerol release is increased in epididymal fat pad adipocytes, indicating enhanced lipolysis

integument

decreased subcutaneous adipose tissue amount ( J:216593 )

• subcutaneous white adipose tissues are smaller

liver/biliary system

decreased liver triglyceride level ( J:216593 )

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Noonan syndrome with multiple lentigines		DOID:14291	OMIM:PS151100	J:216593

Genotype
MGI:3840258

ht7

• Allelic Composition: Ptpn11^tm7Bgn/Ptpn11⁺
• Genetic Background: involves: 129S4/SvJae * 129S6/SvEvTac * C57BL/6

growth/size/body

decreased body weight ( J:147154 )

decreased body length ( J:147154 )

craniofacial

decreased cranium height ( J:147154 )

hematopoietic system

abnormal common myeloid progenitor cell morphology ( J:147154 )

• increase in the number of CFU-GM in the absence of cytokines compared to wild-type controls

skeleton

decreased cranium height ( J:147154 )

Genotype
MGI:3840260

ht8

• Allelic Composition: Ptpn11^tm1Bgn/Ptpn11⁺
• Genetic Background: involves: 129S4/SvJae * C57BL/6

mortality/aging

perinatal lethality, incomplete penetrance ( J:147154 )

• about 50% of mice die either in late gestation or perinatally

• Background Sensitivity: penetrance of lethality is decreased compared to mice on a congenic C57BL/6 background

cardiovascular system

abnormal cardiac epithelial to mesenchymal transition ( J:147154 )

• from 24 - 48 hours in culture endocardial cushions from E9.5 embryos give rise to more mesenchymal cells compared to wild-type controls

• expression analysis indicates that enhanced production of mesenchymal cells is due to a prolongation of the normal interval during which EMT occurs

growth/size/body

decreased body weight ( J:147154 )

decreased body length ( J:147154 )

hematopoietic system

abnormal common myeloid progenitor cell morphology ( J:147154 )

• increase in the number of CFU-GM in the absence of cytokines compared to wild-type controls

vision/eye

increased inner canthal distance ( J:147154 )

• increased inner canthal distance

Genotype
MGI:3050469

ht9

• Allelic Composition: Ptpn11^tm1Bgn/Ptpn11⁺
• Genetic Background: involves: 129S4/SvJae * C57BL/6J

mortality/aging

perinatal lethality, incomplete penetrance ( J:91609 )

• at E18.5 some heterozygous embryos are dead and about 50% fewer than expected heterozygotes are found at weaning

cardiovascular system

abnormal heart development ( J:91609 )

• enlarged atrioventricular valve primordia are seen in about 50% of heterozygotes (severely affected mutants)

double outlet right ventricle ( J:91609 )

• double outlet right ventricle is seen in about 50% of heterozygotes (severely affected mutants)

enlarged mitral valve ( J:91609 )

• enlarged mitral valves are seen in about 50% of heterozygotes (not severely affected) at E13.5 but not at E18.5

ventricular septal defect ( J:91609 )

• at E13.5 ventricular septal defects are seen in about 50% of heterozygotes (severely affected mutants)

cellular

decreased cardiomyocyte apoptosis ( J:91609 )

• decreased apoptosis is seen in endocardial cushions from some heterozygous mutants

increased cell proliferation ( J:91609 )

• increased cellular proliferation is seen in endocardial cushions from some heterozygous mutants

craniofacial

small cranium ( J:91609 )

• consistent with the decreased body size the skull is smaller than normal however width is not different from wild-type resulting in a greater length/width ratio

broad snout ( J:91609 )

• a wider and blunter snout shape is seen

flattened snout ( J:91609 )

• a wider and blunter snout shape is seen

growth/size/body

broad snout ( J:91609 )

• a wider and blunter snout shape is seen

flattened snout ( J:91609 )

• a wider and blunter snout shape is seen

decreased body weight ( J:91609 )

• a significant reduction in body weight and length is seen without altering overall body proportions

decreased body length ( J:91609 )

• a significant reduction in body weight and length is seen without altering overall body proportions

enlarged spleen ( J:91609 )

• older heterozygotes develop splenomegaly with mild myeloid and erythroid hyperplasia

hematopoietic system

enlarged spleen ( J:91609 )

• older heterozygotes develop splenomegaly with mild myeloid and erythroid hyperplasia

myeloid hyperplasia ( J:91609 )

• mild myeloid hyperplasia is seen in the bone marrow of older heterozygotes

increased leukocyte cell number ( J:91609 )

• by 5 months heterozygotes develop mild leukocytosis with normal hematocrit and platelet counts

increased neutrophil cell number ( J:91609 )

increased lymphocyte cell number ( J:91609 )

immune system

enlarged spleen ( J:91609 )

• older heterozygotes develop splenomegaly with mild myeloid and erythroid hyperplasia

myeloid hyperplasia ( J:91609 )

• mild myeloid hyperplasia is seen in the bone marrow of older heterozygotes

increased leukocyte cell number ( J:91609 )

• by 5 months heterozygotes develop mild leukocytosis with normal hematocrit and platelet counts

increased neutrophil cell number ( J:91609 )

increased lymphocyte cell number ( J:91609 )

liver/biliary system

hepatic necrosis ( J:91609 )

• at E13.5 some heterozygotes display mild liver damage

skeleton

small cranium ( J:91609 )

• consistent with the decreased body size the skull is smaller than normal however width is not different from wild-type resulting in a greater length/width ratio

muscle

decreased cardiomyocyte apoptosis ( J:91609 )

• decreased apoptosis is seen in endocardial cushions from some heterozygous mutants

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Noonan syndrome 1		DOID:0060578	OMIM:163950	J:91609

Genotype
MGI:5295463

ht10

• Allelic Composition: Ptpn11^tm1Ckq/Ptpn11⁺
• Genetic Background: involves: 129S6/SvEvTac * C57BL/6J

normal phenotype

no abnormal phenotype detected ( J:177285 )

• mice show no abnormalities

Genotype
MGI:5004709

ht11

• Allelic Composition: Ptpn11^tm4.2Bgn/Ptpn11⁺
• Genetic Background: involves: 129S6/SvEvTac * C57BL/6J * FVB/N

Ptpn11^tm4.2Bgn/Ptpn11⁺ mice demonstrate phenotypic abnormalities similar to those in human Leopard syndrome (LS)

mortality/aging

premature death ( J:172033 )

• by 52 weeks, more mice die than wild-type mice

respiratory system

depressed nasal bridge ( J:172033 )

• planar nasal bridge

reproductive system

abnormal reproductive system morphology ( J:172033 )

• mice exhibit abnormal genitals compared with wild-type mice

cardiovascular system

cardiovascular system phenotype ( J:172033 )

N • mice exhibit normal valvular development and no septal defects

increased myocardial fiber size ( J:172033 )

• adult cardiomyocytes exhibit enlarged area and increased cell width compared to in wild-type mice

• however, rapamycin treatment rescues cardiomyocyte size

thick interventricular septum ( J:172033 )

• at 16 weeks

enlarged heart ( J:172033 )

• by 12 weeks

increased heart weight ( J:172033 )

• at 12 and 16 weeks

• however, treatment with rapamycin rescues heart weight

cardiac hypertrophy ( J:172033 )

• with enlarged nuclei, myofiber disarray, and inflammatory cell accumulation in interstitial fiber

heart left ventricle hypertrophy ( J:172033 )

• by 12 weeks

thick ventricular wall ( J:172033 )

• at 16 weeks, mice exhibit thickened left ventricular free wall compared with wild-type mice

cardiac fibrosis ( J:172033 )

• in older mice

dilated cardiomyopathy ( J:172033 )

• by 52 weeks, with increased diastolic dimension and thinning of the posterior walls

• however, treatment with rapamycin normalizes hypertrophic cardiomyopathy

decreased heart ventricle muscle contractility ( J:172033 )

• at 52 weeks

craniofacial

abnormal cranium size ( J:172033 )

• mice exhibit increased skull width-to-length ratio compared with wild-type mice

abnormal facial morphology ( J:172033 )

• with smaller, more slanted eyes and a planar nasal bridge

depressed nasal bridge ( J:172033 )

• planar nasal bridge

growth/size/body

enlarged heart ( J:172033 )

• by 12 weeks

increased heart weight ( J:172033 )

• at 12 and 16 weeks

• however, treatment with rapamycin rescues heart weight

cardiac hypertrophy ( J:172033 )

• with enlarged nuclei, myofiber disarray, and inflammatory cell accumulation in interstitial fiber

heart left ventricle hypertrophy ( J:172033 )

• by 12 weeks

abnormal facial morphology ( J:172033 )

• with smaller, more slanted eyes and a planar nasal bridge

depressed nasal bridge ( J:172033 )

• planar nasal bridge

abnormal chest morphology ( J:172033 )

• skeletal/chest abnormalities

pectus carinatum ( J:172033 )

• pectus carinatum superiorly

pectus excavatum ( J:172033 )

• pectus excavatum inferiorly

decreased body size ( J:172033 )

• by weaning

skeleton

abnormal cranium size ( J:172033 )

• mice exhibit increased skull width-to-length ratio compared with wild-type mice

short femur ( J:172033 )

vision/eye

abnormal eye distance/ position ( J:172033 )

• smaller, more slanted eyes

ocular hypertelorism ( J:172033 )

• with normal inner canthal distance

hearing/vestibular/ear

abnormal organ of Corti morphology ( J:172033 )

• macrophages accumulate in the organ of Corti unlike in wild-type mice

hematopoietic system

hematopoietic system phenotype ( J:172033 )

N • mice exhibit normal hematological parameters

limbs/digits/tail

short femur ( J:172033 )

muscle

increased myocardial fiber size ( J:172033 )

• adult cardiomyocytes exhibit enlarged area and increased cell width compared to in wild-type mice

• however, rapamycin treatment rescues cardiomyocyte size

heart left ventricle hypertrophy ( J:172033 )

• by 12 weeks

dilated cardiomyopathy ( J:172033 )

• by 52 weeks, with increased diastolic dimension and thinning of the posterior walls

• however, treatment with rapamycin normalizes hypertrophic cardiomyopathy

decreased heart ventricle muscle contractility ( J:172033 )

• at 52 weeks

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Noonan syndrome with multiple lentigines		DOID:14291	OMIM:PS151100	J:172033

Genotype
MGI:6095197

cn12

• Allelic Composition: Emx1^tm1(cre)Krj/Emx1⁺; Ptpn11^tm6Bgn/Ptpn11⁺
• Genetic Background: B6.129S-Ptpn11^tm6Bgn Emx1^tm1(cre)Krj

behavior/neurological

impaired cued conditioning behavior ( J:242312 )

• during auditory cued retrieval, mice show a reduced ability to discriminate conditional stimuli of 10-kHZ, 10 seconds with 20 seconds inter stimulus intervals (CS+) and conditional stimuli of 2.5-kHz, 10 seconds with 20 seconds inter stimulus intervals (CS-), with response to CS+ slightly reduced and to CS- somewhat increased

• however, mice exhibit normal levels of contextual fear memory

decreased exploration in new environment ( J:242312 )

• mice exhibit reduced exploratory behavior in the open field task, with a shorter run distance than controls

abnormal spatial learning ( J:242312 )

• in the Morris water maze, mice show a reduced path length during training and lower average speed resulting in similar escape latencies as controls, and reduced total distance traveled during probe trial 1, indicating reduced memory specificity

nervous system

abnormal hippocampus neuron morphology ( J:242312 )

• surface expression and trafficking of synaptic glutamate receptors is altered in hippocampal neurons, indicating possible hippocampal neuronal plasticity defects

• however, axonal outgrowth and dendritic arborization in cultured hippocampal neurons is similar to controls and synaptogenesis appears normal

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Noonan syndrome 1		DOID:0060578	OMIM:163950	J:242312

Genotype
MGI:5295466

cn13

• Allelic Composition: Cd19^tm1(cre)Cgn/Cd19⁺; Ptpn11^tm1Ckq/Ptpn11⁺
• Genetic Background: involves: 129P2/OlaHsd * 129S6/SvEvTac * C57BL/6J

mortality/aging

premature death ( J:177285 )

neoplasm

increased acute lymphoblastic leukemia incidence ( J:177285 )

• B cell lymphoblastic leukemia/lymphoma in 4 of 9 mice

increased B cell derived lymphoma incidence ( J:177285 )

• B cell lymphoblastic leukemia/lymphoma in 4 of 9 mice

Genotype
MGI:5295468

cn14

• Allelic Composition: Ptpn11^tm1Ckq/Ptpn11⁺; Lyz2^tm1(cre)Ifo/Lyz2⁺
• Genetic Background: involves: 129P2/OlaHsd * 129S6/SvEvTac * C57BL/6J

mortality/aging

premature death ( J:177285 )

neoplasm

increased acute promyelocytic leukemia incidence ( J:177285 )

• acute myeloid leukemia in 4 of 10 mice

immune system

myeloid hyperplasia ( J:177285 )

• all mice develop myeloproliferative disease with enhanced myeloid cell proliferation and differentiation

• 2 of 10 mice develop accelerated myeloproliferative disease

hematopoietic system

myeloid hyperplasia ( J:177285 )

• all mice develop myeloproliferative disease with enhanced myeloid cell proliferation and differentiation

• 2 of 10 mice develop accelerated myeloproliferative disease

Genotype
MGI:5295464

cn15

• Allelic Composition: Hprt1^{tm1(CAG-cre)Mnn}/Hprt1⁺; Ptpn11^tm1Ckq/Ptpn11⁺
• Genetic Background: involves: 129S1/Sv * 129S6/SvEvTac * C57BL/6J

Embryonic lethality in Ptpn11^tm1Ckq/Ptpn11⁺ Hprt1^{tm1(CAG-cre)Mnn}/Hprt1⁺ mice

mortality/aging

embryonic lethality during organogenesis, complete penetrance ( J:177285 )

♀ • mice die around E11.5

embryo

embryonic growth retardation ( J:177285 )

♀ • at E9.5

cardiovascular system

abnormal heart tube morphology ( J:177285 )

♀ • enlarged

craniofacial

abnormal craniofacial development ( J:177285 )

♀

growth/size/body

embryonic growth retardation ( J:177285 )

♀ • at E9.5

Genotype
MGI:3840253

cn16

• Allelic Composition: Meox2^tm1(cre)Sor/Meox2⁺; Ptpn11^tm6Bgn/Ptpn11⁺
• Genetic Background: involves: 129S4/SvJaeSor * 129S6/SvEvTac * C57BL/6

cardiovascular system

abnormal heart morphology ( J:147154 )

• all mice show cardiac defects

thin myocardium ( J:147154 )

double outlet right ventricle ( J:147154 )

atrial septal defect ( J:147154 )

ventricular septal defect ( J:147154 )

• ventricular septal defect

heart valve hyperplasia ( J:147154 )

muscle

thin myocardium ( J:147154 )

Genotype
MGI:3840254

cn17

• Allelic Composition: Ptpn11^tm6Bgn/Ptpn11⁺; Tg(Tek-cre)12Flv/0
• Genetic Background: involves: 129S6/SvEvTac * C3H * C57BL/6

mortality/aging

embryonic lethality ( J:147154 )

cardiovascular system

thin myocardium ( J:147154 )

• seen at E13.5

increased atrioventricular cushion size ( J:147154 )

• seen at E11.5 and E13.5

double outlet right ventricle ( J:147154 )

ventricular septal defect ( J:147154 )

muscle

thin myocardium ( J:147154 )

• seen at E13.5

Genotype
MGI:5295465

cn18

• Allelic Composition: Ptpn11^tm1Ckq/Ptpn11⁺; Tg(Mx1-cre)1Cgn/0
• Genetic Background: involves: 129S6/SvEvTac * C57BL/6 * C57BL/6J * CBA

Increased spleen weight in Ptpn11^tm1Ckq/Ptpn11⁺ Tg(Mx1-cre)1Cgn/0 mice

mortality/aging

premature death ( J:177285 )

• by 56 weeks due to leukemia in pIpC-treated mice

hematopoietic system

increased lymphoblastic lymphoma incidence ( J:177285 )

• T cell lymphoblastic leukemia/lymphoma in 9 of 27 pIpC-treated mice

enlarged spleen ( J:177285 )

• in pIpC-treated mice

increased spleen weight ( J:177285 )

• in pIpC-treated mice

arrested B cell differentiation ( J:177285 )

• around the pro-B stage in pIpC-treated mice

myeloid hyperplasia ( J:177285 )

• all pIpC-treated mice develop myeloproliferative disease (MPD)

• Mac-1+/Gr-1+ mature myeloid cells are increased

• 5 of 27 pIpC-treated mice exhibit accelerated MPD

extramedullary hematopoiesis ( J:177285 )

• hyperproliferation in the liver and spleen in pIpC-treated mice

anemia ( J:177285 )

• progressive in pIpC-treated mice

abnormal bone marrow cell morphology/development ( J:177285 )

• pIpC-treated mice exhibit decreased common myeloid progenitors, granulocyte macrophage progenitors, and megakaryocyte erythroid progenitors compared with wild-type mice

• however, common lymphoid progenitor numbers are normal

decreased common myeloid progenitor cell number ( J:177285 )

• in pIpC-treated mice

increased leukocyte cell number ( J:177285 )

• extremely high after 32 weeks with leukemia infiltration in nonhematopoietic organs of pIpC-treated mice

increased neutrophil cell number ( J:177285 )

• in pIpC-treated mice

decreased hematopoietic stem cell number ( J:177285 )

• 3-fold in the bone marrow in pIpC-treated mice

increased hematopoietic stem cell number ( J:177285 )

• in the spleen of pIpC-treated mice

abnormal hematopoietic stem cell physiology ( J:177285 )

• hematopoietic stem cells are hyperactivated in pIpC-treated mice

• hematopoietic stem cell quiescent in pIpC-treated mice is decreased 2-fold while the S and G2/M phase were doubled compared to in wild-type mice

• apoptosis of hematopoietic stem cells in pIpC-treated mice is decreased compared to in wild-type mice

neoplasm

increased lymphoblastic lymphoma incidence ( J:177285 )

• T cell lymphoblastic leukemia/lymphoma in 9 of 27 pIpC-treated mice

increased leukemia incidence ( J:177285 )

• after 12 to 32 weeks of chronic myeloproliferative disease in pIpC-treated mice

increased acute lymphoblastic leukemia incidence ( J:177285 )

• B and T cell lymphoblastic leukemia/lymphoma in pIpC-treated mice

increased acute promyelocytic leukemia incidence ( J:177285 )

• acute myeloid leukemia in 6 of 27 pIpC-treated mice

increased B cell derived lymphoma incidence ( J:177285 )

• B cell lymphoblastic leukemia/lymphoma in 2 of 27 pIpC-treated mice

cellular

aneuploidy ( J:177285 )

• in bone marrow cells and splenocytes from pIpC-treated mice

chromosomal instability ( J:177285 )

• in pIpC-treated mice due to centrosome amplification

liver/biliary system

enlarged liver ( J:177285 )

• in pIpC-treated mice

immune system

increased lymphoblastic lymphoma incidence ( J:177285 )

• T cell lymphoblastic leukemia/lymphoma in 9 of 27 pIpC-treated mice

enlarged spleen ( J:177285 )

• in pIpC-treated mice

increased spleen weight ( J:177285 )

• in pIpC-treated mice

arrested B cell differentiation ( J:177285 )

• around the pro-B stage in pIpC-treated mice

myeloid hyperplasia ( J:177285 )

• all pIpC-treated mice develop myeloproliferative disease (MPD)

• Mac-1+/Gr-1+ mature myeloid cells are increased

• 5 of 27 pIpC-treated mice exhibit accelerated MPD

increased leukocyte cell number ( J:177285 )

• extremely high after 32 weeks with leukemia infiltration in nonhematopoietic organs of pIpC-treated mice

increased neutrophil cell number ( J:177285 )

• in pIpC-treated mice

endocrine/exocrine glands

increased lymphoblastic lymphoma incidence ( J:177285 )

• T cell lymphoblastic leukemia/lymphoma in 9 of 27 pIpC-treated mice

growth/size/body

enlarged liver ( J:177285 )

• in pIpC-treated mice

enlarged spleen ( J:177285 )

• in pIpC-treated mice

increased spleen weight ( J:177285 )

• in pIpC-treated mice

Genotype
MGI:3845013

cn19

• Allelic Composition: Ptpn11^tm6Bgn/Ptpn11⁺; Tg(CAG-cre/Esr1*)5Amc/0
• Genetic Background: involves: 129S6/SvEvTac * C57BL/6 * CBA

hematopoietic system

abnormal definitive hematopoiesis ( J:148430 )

• following tamoxifen treatment cultured bone marrow megakaryocyte-erythrocyte progenitor cells produce significantly fewer erythrocyte colony-forming unit colonies and slightly more erythroid burst-forming unit colonies

abnormal leukopoiesis ( J:148430 )

• following tamoxifen treatment cultured granulocyte-monocyte progenitor cells and common myeloid progenitor cells give rise to more cytokine independent colonies

immune system

abnormal leukopoiesis ( J:148430 )

• following tamoxifen treatment cultured granulocyte-monocyte progenitor cells and common myeloid progenitor cells give rise to more cytokine independent colonies

Genotype
MGI:3845014

cn20

• Allelic Composition: Ptpn11^tm6Bgn/Ptpn11⁺; Tg(Mx1-cre)1Cgn/0
• Genetic Background: involves: 129S6/SvEvTac * C57BL/6 * CBA

mortality/aging

premature death ( J:148430 )

• all mice die within 45 weeks after receiving pIpC injections

hematopoietic system

enlarged spleen ( J:148430 )

• following pIpC injections mice develop splenomegaly

abnormal definitive hematopoiesis ( J:148430 )

• following pIpC injections cultured bone marrow megakaryocyte-erythrocyte progenitor cells produce fewer erythrocyte colony-forming unit colonies and more, larger erythroid burst-forming unit colonies

• the myeloproliferative disorder seen after pIpC injections does not develop in irradiated mice engrafted with cells from diseased mice

decreased common myeloid progenitor cell number ( J:148430 )

• following pIpC injections common myeloid progenitor cell numbers are reduced in the bone marrow

abnormal erythropoiesis ( J:148430 )

• following pIpC injections cultured erythroid progenitors produce fewer erythrocyte colony-forming unit colonies

abnormal leukopoiesis ( J:148430 )

• following pIpC injections both bone marrow and spleen cells form increased numbers of cytokine independent colonies that are primarily macrophage colony forming units and granulocyte colony forming units

extramedullary hematopoiesis ( J:148430 )

• following pIpC injections mice develop marked extramedullary hematopoiesis with an increase in the numbers of long term and short term hematopoietic stem cells and granulocyte-monocyte progenitor cells following pIpC injections

anemia ( J:148430 )

• following pIpC injections mice develop anemia

abnormal bone marrow cell number ( J:148430 )

• following pIpC injections increased numbers of immature predominantly granulocytic cells are found in the bone marrow

decreased bone marrow cell number ( J:148430 )

• following pIpC injections total bone marrow cellularity is decreased

decreased granulocyte monocyte progenitor cell number ( J:148430 )

• following pIpC injections granulocyte-monocyte progenitor cell numbers are reduced in the bone marrow

increased leukocyte cell number ( J:148430 )

• following pIpC injections mice develop progressive leukocytosis

increased granulocyte number ( J:148430 )

• following pIpC injections mice develop progressive granulocytosis

increased monocyte cell number ( J:148430 )

• following pIpC injections mice develop progressive monocytosis

decreased hematopoietic stem cell number ( J:148430 )

• following pIpC injections the sizes of the Lin-Sca1+cKit+ (LSK) and Lin-Sca1-cKit+ (LK) compartments in the bone marrow are reduced

• following pIpC injections fewer cells in the LSK compartment are quiescent and these cells are hypersensitive to stem cell factor

• following pIpC injections the number of long term hematopoietic stem cells is reduced

intermingled spleen red and white pulp ( J:148430 )

• following pIpC injections infiltration of mature myeloid cells into the red pulp is seen

abnormal splenic cell ratio ( J:148430 )

• following pIpC injections the ratio of Mac1+Gr1+ cells is increased 9 to 10 fold, the ratio of erythroid progenitors is increased 6 to 7 fold, and the relative number of T cells is decreased

liver/biliary system

abnormal liver sinusoid morphology ( J:148430 )

• following pIpC injections periportal cuffing of liver sinusoids with infiltrating granulocytes is seen

enlarged liver ( J:148430 )

• following pIpC injections mice develop hepatomegaly

immune system

enlarged spleen ( J:148430 )

• following pIpC injections mice develop splenomegaly

abnormal leukopoiesis ( J:148430 )

• following pIpC injections both bone marrow and spleen cells form increased numbers of cytokine independent colonies that are primarily macrophage colony forming units and granulocyte colony forming units

increased leukocyte cell number ( J:148430 )

• following pIpC injections mice develop progressive leukocytosis

increased granulocyte number ( J:148430 )

• following pIpC injections mice develop progressive granulocytosis

increased monocyte cell number ( J:148430 )

• following pIpC injections mice develop progressive monocytosis

intermingled spleen red and white pulp ( J:148430 )

• following pIpC injections infiltration of mature myeloid cells into the red pulp is seen

abnormal splenic cell ratio ( J:148430 )

• following pIpC injections the ratio of Mac1+Gr1+ cells is increased 9 to 10 fold, the ratio of erythroid progenitors is increased 6 to 7 fold, and the relative number of T cells is decreased

cardiovascular system

abnormal liver sinusoid morphology ( J:148430 )

• following pIpC injections periportal cuffing of liver sinusoids with infiltrating granulocytes is seen

growth/size/body

enlarged liver ( J:148430 )

• following pIpC injections mice develop hepatomegaly

enlarged spleen ( J:148430 )

• following pIpC injections mice develop splenomegaly

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
juvenile myelomonocytic leukemia		DOID:0050458	OMIM:607785	J:148430

Genotype
MGI:3840256

cn21

• Allelic Composition: Ptpn11^tm6Bgn/Ptpn11⁺; H2az2^{Tg(Wnt1-cre)11Rth}/H2az2⁺
• Genetic Background: involves: 129S6/SvEvTac * C57BL/6 * CBA/J

cardiovascular system

cardiovascular system phenotype ( J:147154 )

N • no cardiac defects are seen

craniofacial

decreased cranium height ( J:147154 )

vision/eye

increased inner canthal distance ( J:147154 )

• increased inner canthal distance

skeleton

decreased cranium height ( J:147154 )

Genotype
MGI:3840255

cn22

• Allelic Composition: Ptpn11^tm6Bgn/Ptpn11⁺; Tg(Myh6-cre)2182Mds/0
• Genetic Background: involves: 129S6/SvEvTac * C57BL/6 * FVB/N

cardiovascular system

cardiovascular system phenotype ( J:147154 )

N • no gross cardiac defects are seen

Genotype
MGI:5295469

cn23

• Allelic Composition: Ptpn11^tm1Ckq/Ptpn11⁺; Tg(Lck-cre)1Cwi/0
• Genetic Background: involves: 129S6/SvEvTac * C57BL/6J

endocrine/exocrine glands

increased lymphoblastic lymphoma incidence ( J:177285 )

• T cell lymphoblastic leukemia/lymphoma in 8 of 15 mice

mortality/aging

premature death ( J:177285 )

neoplasm

increased lymphoblastic lymphoma incidence ( J:177285 )

• T cell lymphoblastic leukemia/lymphoma in 8 of 15 mice

increased acute lymphoblastic leukemia incidence ( J:177285 )

• T cell lymphoblastic leukemia/lymphoma in 8 of 15 mice

immune system

immune system phenotype ( J:177285 )

N • T and B cell development is normal

increased lymphoblastic lymphoma incidence ( J:177285 )

• T cell lymphoblastic leukemia/lymphoma in 8 of 15 mice

hematopoietic system

increased lymphoblastic lymphoma incidence ( J:177285 )

• T cell lymphoblastic leukemia/lymphoma in 8 of 15 mice

Genotype
MGI:3845015

cn24

• Allelic Composition: Ptpn11^tm6Bgn/Ptpn11⁺; Tg(EIIa-cre)C5379Lmgd/0
• Genetic Background: involves: 129S6/SvEvTac * FVB/N

mortality/aging

preweaning lethality, complete penetrance ( J:148430 )

• no viable recombinants are found

Genotype
MGI:2176546

cx25

• Allelic Composition: Egfr^wa2/Egfr^wa2; Ptpn11^tm1Rbn/Ptpn11⁺
• Genetic Background: involves: 129 * B6EiC3Sn-a/A-Egfr^wa2 Wnt3a^vt

muscle

myocardium hypertrophy ( J:60750 )

• develop myocardial hypertrophy

mortality/aging

perinatal lethality, incomplete penetrance ( J:60750 )

• fewer mutants than predicted are seen at P10, however observe no deaths between P1 and P10, indicating embryonic lethality or death soon after birth

cardiovascular system

myocardium hypertrophy ( J:60750 )

• develop myocardial hypertrophy

aortic valve stenosis ( J:60750 )

• valve abnormalities persist into adulthood causing mild to moderate aortic stenosis

thick aortic valve ( J:60750 )

• aortic valve is thickened

thick pulmonary valve ( J:60750 )

• pulmonary valve is thickened

enlarged semilunar valve ( J:60750 )

• exhibit semilunar valve enlargement resulting from over-abundant mesenchymal cells

• however, atrioventricular valves and interventricular septum are unaffected

aortic valve regurgitation ( J:60750 )

• valve abnormalities persist into adulthood causing moderate to severe regurgitation

increased left ventricle diastolic pressure ( J:60750 )

• elevation in left-ventricular-end-diastolic pressures, reflecting diastolic dysfunction and possibly incipient heart failure

increased left ventricle systolic pressure ( J:60750 )

• higher peak left ventricular systolic pressure and a trend towards increased +dP/dT

abnormal impulse conducting system conduction ( J:60750 )

• severe conduction system abnormalities

prolonged RR interval ( J:60750 )

prolonged PR interval ( J:60750 )

prolonged QRS complex duration ( J:60750 )

• slightly prolonged QRS

prolonged QT interval ( J:60750 )

prolonged ST segment ( J:60750 )

• prolonged ST interval

increased systemic arterial blood pressure ( J:60750 )

congestive heart failure ( J:60750 )

• occasionally show cardiac dilation characteristic of congestive heart failure

vision/eye

eyelids open at birth ( J:60750 )

• display defective eyelid closure

growth/size/body

myocardium hypertrophy ( J:60750 )

• develop myocardial hypertrophy

Genotype
MGI:2176569

cx26

• Allelic Composition: Egfr^wa2/Egfr^wa2; Ptpn11^tm1Paw/Ptpn11⁺
• Genetic Background: involves: 129S1/Sv * 129X1/SvJ * B6EiC3Sn a/A-Egfr^wa2 Wnt3a^vt * C57BL/6

Defects in the skin, lung and intestine of Egfr^wa2/Egfr^wa2 Ptpn11^tm1Paw/⁺ mice

mortality/aging

postnatal lethality, incomplete penetrance ( J:75413 )

• only 30% survive to weaning, with most dying within 7-10 days after birth

growth/size/body

cachexia ( J:75413 )

• exhibit progressive wasting

postnatal growth retardation ( J:75413 )

muscle

intestinal hypoperistalsis ( J:75413 )

• lumen of stomach and small and large bowels are filled with desquamated epithelial cells, suggesting lack of peristalsis

abnormal muscle morphology ( J:75413 )

• decrease in the size of subcutaneous muscle tissue

respiratory system

abnormal lung development ( J:75413 )

• lungs are immaturely developed with poorly inflated areas

atelectasis ( J:75413 )

thick pulmonary interalveolar septum ( J:75413 )

• increase in thickness and cell masses of the alveolar septae

abnormal breathing pattern ( J:75413 )

• display breathing difficulties

vision/eye

eyelids open at birth ( J:75413 )

adipose tissue

decreased subcutaneous adipose tissue amount ( J:75413 )

• decrease in the size of subcutaneous fat tissue

digestive/alimentary system

abnormal intestine morphology ( J:75413 )

• the muscle layer of the bowel is poorly organized and is decreased in thickness

intestinal hypoperistalsis ( J:75413 )

• lumen of stomach and small and large bowels are filled with desquamated epithelial cells, suggesting lack of peristalsis

integument

decreased subcutaneous adipose tissue amount ( J:75413 )

• decrease in the size of subcutaneous fat tissue

abnormal hair growth ( J:75413 )

• little hair outgrowth

waved hair ( J:75413 )

abnormal hair follicle morphology ( J:75413 )

abnormal hair follicle development ( J:75413 )

• poorly developed hair follicles

abnormal hair follicle orientation ( J:75413 )

• hair follicles are disordered

decreased hair follicle number ( J:75413 )

• skin contains no or few disorganized hair follicles

epidermal atrophy ( J:75413 )

• hypotrophy in the epidermis

thin epidermis ( J:75413 )

dry skin ( J:75413 )

• skin gradually becomes dry and flaky

flaky skin ( J:75413 )

• skin gradually becomes dry and flaky

abnormal skin condition ( J:75413 )

thin skin ( J:75413 )