Overview

Also Known As:Sos1^E846K

These Sos1^E846K mice exhibit phenotypes consistent with several features of Noonan syndrome including: cardiac hypertrophy, short stature, triangular faces and blunt snouts, splenomegaly, and hematologic disorders. Most homozygous embryos die due to cardiac defects.

Donating Investigator

Benjamin Neel, NYU School of Medicine

Genetic overview

Genetic Background	Generation

Sos1^tm1.2Rak

Allele Type	Gene Symbol	Gene Name
Targeted (Humanized sequence)	Sos1	SOS Ras/Rac guanine nucleotide exchange factor 1

View Genetics

Research Applications

Internal/Organ Research
Hematological Research
Developmental Biology Research
Cardiovascular Research

View All Research Applications

Details

Detailed Description

SOS1 (son of sevenless homolog 1) encodes a RAS and RAC guanine nucleotide exchange factor (GEF) and is involved regulation of the RAS/ERK/MAPK pathway. Mutations in this gene are associated with Noonan syndrome (NS), an autosomal dominant disorder characterized by with congenital heart disease, short stature, facial abnormalities and myeloproliferative disease. 10-15% of NS patients have mutations in Sos1. The E846K allele is a missense mutation that causes a conformational change resulting in constitutive activation of the RAS/MAPK pathway.

Most homozygous embryos die between E10.5 and the neonatal stage from multiple cardiac defects including atrial/ventricular septal defects, aortic valvular stenosis, ventricular hypertrophy and pericardial effusions. Surviving homozygous mice do not live beyond 10 months of age.
Heterozygotes exhibit left ventricular cardiac hypertrophy, short stature, shortened skull length with triangular faces and blunt snouts, splenomegaly, and increased numbers of neutrophils and leukocytes.

Development

The targeting vector is designed as a unidirectional Cre-mediated recombination system. The vector contains a wild-type loxP (wloxP) site upstream of exon 16, a mutant loxP (mloxP) site downstream of exon 16, an inverted exon 16 with the amino acid substitution E846K, followed by wloxP and mloxP sites and an FRT-flanked neomycin cassette. The mloxP sites preferentially recombine with each other, as do the wloxP sites. The E846K mutation results in a glutamic acid to lysine change at position 846. The construct was electroporated into 129S4/SvJae –derived J1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts. The resulting chimeric animals were crossed to B6.Cg-Tg(ACTFLPe)9205Dym/J to remove the neomycin cassette, followed by a cross to unspecified EIIA-cre mice on a C57BL/6 background .
Following Cre exposure, the inverted exon 16 (with the E846K mutation) moved into the correct orientation and the endogenous exon 16 was removed.

Heterozygous mice were mated and offspring lacking the Cre transgene were crossed to C57BL/6 mice for at least 10 generations. Upon arrival, mice were bred to C57BL/6J for at least 1 generation to establish the colony.

Control Suggestions

Wild-type littermate
000664 C57BL/6J

Additional Information

Considerations for Choosing Controls

Selected References

Chen PC; Wakimoto H; Conner D; Araki T; Yuan T; Roberts A; Seidman CE; Bronson R; Neel BG; Seidman JG; Kucherlapati R. 2010. Activation of multiple signaling pathways causes developmental defects in mice with a Noonan syndrome-associated Sos1 mutation. J Clin Invest 120(12):4353-65PubMed: 21041952 MGI: J:171873

View All References

Genetics

Sos1^tm1.2Rak

Allele Symbol: Sos1^tm1.2Rak

Allele Name	targeted mutation 1.2, Raju Kucherlapati
Allele Type	Targeted (Humanized sequence)
Allele Synonym(s)	Sos1^E846K; Sos1E846K
Gene Symbol and Name	Sos1, SOS Ras/Rac guanine nucleotide exchange factor 1
Gene Synonym(s)
Strain of Origin	129S4/SvJae
Chromosome	17
Molecular Note	A wloxP site was inserted upstream of exon 16. An inverted segment that contained an mloxP flanked, modified exon 16 with an upstream wloxP site and an FRT-flanked neo cassette was inserted downstream of exon 16. The modified exon 16 contains an C to T transition that results in an glutamic acid to lysine at position 846 (E486K, equivalent to a mutation found in Noonan syndrome (NS) patients). Flp-mediated recombination removed the neo cassette. Cre-mediated recombination rearranged the modified exon 16 into correct orientation and removed the endogenous exon 16.

Disease/Phenotype

Disease Terms

Model with phenotypic similarity to human disease where etiologies involve orthologs. Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

Noonan syndrome 4

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Internal/Organ Research
- Spleen Defects
Hematological Research
Developmental Biology Research
- Craniofacial and Palate Defects
- Growth Defects
- Internal/Organ Defects
  - heart
- Embryonic Lethality (Homozygous)
  - incomplete
Cardiovascular Research
- Heart Abnormalities

Mammalian Phenotype Terms by Genotype

The following phenotype information is associated with a similar, but not exact match to this JAX^® Mice strain

Genotype: Sos1^tm1.2Rak/Sos1^tm1.2Rak
involves: 129S/Sv * C57BL/6 * FVB/N * SJL

cellular phenotype

abnormal fetal cardiomyocyte proliferation
- at E15.5, mice exhibit increased proliferation and decreased apoptosis in the interventricular septal and aortic valve tissues compared with wild-type mice

craniofacial phenotype

abnormal craniofacial morphology
- at 3 months, mice exhibit a tend towards triangular faces with blunter snouts because of depression of the anterior frontal bone compared with wild-type mice
- Normal - however, treatment with PD0325901 improves facial dysmorphia

abnormal frontal bone morphology
- at 3 months, mice exhibit depression of the anterior frontal bone compared with wild-type mice

decreased cranium height
- at 3 months

growth/size/body region phenotype

decreased body size

decreased body weight
- however, treatment with PD0325901 improves body weight

heart right ventricle hypertrophy
- at E15.5

decreased body length

homeostasis/metabolism phenotype

pericardial effusion
- at E15.5

skin edema

integument phenotype

skin edema

mortality/aging

embryonic lethality during organogenesis, incomplete penetrance
- fewer than expected mice are present at E10.5 and E13.5
- Normal - however, treatment with the MEK inhibitor PD0325901 improves embryonic lethality

premature death
- mice that survive birth die exhibit premature lethality

lethality throughout fetal growth and development, incomplete penetrance
- fewer than expected mice are present at E15.5

muscle phenotype

heart right ventricle hypertrophy
- at E15.5

abnormal fetal cardiomyocyte proliferation
- at E15.5, mice exhibit increased proliferation and decreased apoptosis in the interventricular septal and aortic valve tissues compared with wild-type mice

myocardial fiber degeneration

skeleton phenotype

abnormal frontal bone morphology
- at 3 months, mice exhibit depression of the anterior frontal bone compared with wild-type mice

decreased cranium height
- at 3 months

vision/eye phenotype

ocular hypertelorism
- at 3 months

cardiovascular system phenotype

hemorrhage
- mice exhibit subcutaneous hemorrhage unlike wild-type mice

ostium secundum atrial septal defect
- at E15.5

thick aortic valve cusps
- at E15.5 and at 3 months

abnormal cardiovascular system physiology
- at E15.5, mice exhibit increased proliferation and decreased apoptosis in the interventricular septal and aortic valve tissues compared with wild-type mice

ventricular septal defect
- at E15.5

abnormal heart morphology
- Normal - however, mice treated with PD0325901 exhibit no anatomical heart abnormalities
- mice exhibit adipocyte infiltration in the ventricular myocardium and the surrounding blood vessels unlike in wild-type mice

aortic valve stenosis
- at E15.5 and at 3 months due to thickened leaflets

abnormal fetal cardiomyocyte proliferation
- at E15.5, mice exhibit increased proliferation and decreased apoptosis in the interventricular septal and aortic valve tissues compared with wild-type mice

pericardial effusion
- at E15.5

thick interventricular septum

myocardial fiber degeneration

cardiac fibrosis
- at 3 months, mice exhibit epicardial and myocardial fibrosis unlike wild-type mice

heart right ventricle hypertrophy
- at E15.5

Genotype: Sos1^tm1.2Rak/Sos1⁺
involves: 129S/Sv * C57BL/6 * FVB/N * SJL

cellular phenotype

abnormal fetal cardiomyocyte proliferation
- at E15.5, mice exhibit increased proliferation and decreased apoptosis in the interventricular septal and aortic valve tissues compared with wild-type mice

increased cardiomyocyte apoptosis

craniofacial phenotype

abnormal frontal bone morphology
- at 3 months, mice exhibit depression of the anterior frontal bone compared with wild-type mice

decreased cranium height
- at 3 months

abnormal craniofacial morphology
- at 3 months, mice exhibit a tend towards triangular faces with blunter snouts because of depression of the anterior frontal bone compared with wild-type mice
- Normal - however, treatment with PD0325901 improves facial dysmorphia

growth/size/body region phenotype

enlarged spleen
- by 5 months

heart left ventricle hypertrophy
- mice exhibit increased left ventricular end-diastolic diameter compared with wild-type mice

decreased body length

decreased body size

decreased body weight
- however, treatment with PD0325901 improves body weight

hematopoietic system phenotype

enlarged spleen
- by 5 months

increased megakaryocyte cell number
- by 5 months

increased spleen red pulp amount

increased neutrophil cell number
- in some mice

abnormal common myeloid progenitor cell morphology
- bone marrow cells treated with GM-CSF or IL3 produce increased myeloid colony formation compared with wild-type cells
- mice exhibit increased myeloid cells in the bone marrow and spleen compared with wild-type mice

increased leukocyte cell number
- subtle at 5 months

abnormal erythropoiesis
- by 5 months, mice exhibit increased erythropoiesis compared with wild-type mice

extramedullary hematopoiesis
- by 5 months

homeostasis/metabolism phenotype

pericardial effusion
- in some mice

skin edema
- in some mice

immune system phenotype

increased neutrophil cell number
- in some mice

increased spleen red pulp amount

increased leukocyte cell number
- subtle at 5 months

enlarged spleen
- by 5 months

integument phenotype

skin edema
- in some mice

mammalian phenotype

cardiovascular system phenotype
- Normal - mice exhibit normal blood pressure

muscle phenotype

heart left ventricle hypertrophy
- mice exhibit increased left ventricular end-diastolic diameter compared with wild-type mice

increased cardiomyocyte apoptosis

abnormal fetal cardiomyocyte proliferation
- at E15.5, mice exhibit increased proliferation and decreased apoptosis in the interventricular septal and aortic valve tissues compared with wild-type mice

enlarged myocardial fiber

abnormal myocardial fiber morphology
- irregularly shaped

skeleton phenotype

decreased cranium height
- at 3 months

abnormal frontal bone morphology
- at 3 months, mice exhibit depression of the anterior frontal bone compared with wild-type mice

vision/eye phenotype

ocular hypertelorism
- at 3 months

cardiovascular system phenotype

cardiac interstitial fibrosis

hemorrhage
- in some mice

abnormal cardiovascular system physiology
- at E15.5, mice exhibit increased proliferation and decreased apoptosis in the interventricular septal and aortic valve tissues compared with wild-type mice

abnormal heart left ventricle morphology
- mice exhibit increased left ventricular end-diastolic diameter compared with wild-type mice

abnormal fetal cardiomyocyte proliferation
- at E15.5, mice exhibit increased proliferation and decreased apoptosis in the interventricular septal and aortic valve tissues compared with wild-type mice

aortic valve stenosis
- in some mice at 8.5 months of age due to thickened leaflets

enlarged myocardial fiber

increased cardiomyocyte apoptosis

cardiac fibrosis
- mice exhibit severe focal and interstitial fibrosis unlike wild-type mice

thick aortic valve cusps

abnormal heart morphology
- mice exhibit some adipocyte infiltration in the heart unlike in wild-type mice

abnormal myocardial fiber morphology
- irregularly shaped

heart left ventricle hypertrophy
- mice exhibit increased left ventricular end-diastolic diameter compared with wild-type mice

pericardial effusion
- in some mice

thick interventricular septum

References

Chen PC; Wakimoto H; Conner D; Araki T; Yuan T; Roberts A; Seidman CE; Bronson R; Neel BG; Seidman JG; Kucherlapati R. 2010. Activation of multiple signaling pathways causes developmental defects in mice with a Noonan syndrome-associated Sos1 mutation. J Clin Invest 120(12):4353-65PubMed: 21041952 MGI: J:171873

Additional - Sos1^tm1.2Rak related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Sanger sequencing:Sos1alternate1
- Genotyping resources and troubleshooting
Breeding Considerations

While maintaining a live colony, these mice are bred as heterozygotes. Most homozygous embryos die due to cardiac defects.
- Additional Breeding and Husbandry Support
Citation
When using the Sos1^E846K mouse strain in a publication, please cite the originating article(s) and include MMRRC stock #37588 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

The Jackson Laboratory's Genotype Promise

The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project. We do not guarantee breeding performance and therefore suggest that investigators order more than one breeding pair to avoid delays in their research.

Terms Of Use

General Terms and Conditions

See MMRRC for Additional Conditions of Distribution

Questions about Terms of Use

Licensing Information

Phone: 207-288-6470

Email: TechTran@jax.org

Also Known As:Sos1E846K

Donating Investigator

Genetic overview

Research Applications

Detailed Description

Development

Control Suggestions

Additional Information

Selected References

Sos1tm1.2Rak

Allele Symbol: Sos1tm1.2Rak

Disease Terms

Model with phenotypic similarity to human disease where etiologies involve orthologs. Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

Research Areas By Phenotype

This mouse can be used to support research in many areas including:

Mammalian Phenotype Terms by Genotype

Genotype: Sos1tm1.2Rak/Sos1tm1.2Rakinvolves: 129S/Sv * C57BL/6 * FVB/N * SJL

cellular phenotype

craniofacial phenotype

growth/size/body region phenotype

homeostasis/metabolism phenotype

integument phenotype

mortality/aging

muscle phenotype

skeleton phenotype

vision/eye phenotype

cardiovascular system phenotype

Genotype: Sos1tm1.2Rak/Sos1+involves: 129S/Sv * C57BL/6 * FVB/N * SJL

cellular phenotype

craniofacial phenotype

growth/size/body region phenotype

hematopoietic system phenotype

homeostasis/metabolism phenotype

immune system phenotype

integument phenotype

mammalian phenotype

muscle phenotype

skeleton phenotype

vision/eye phenotype

cardiovascular system phenotype

References

Additional - Sos1tm1.2Rak related

Genotyping Protocols

Breeding Considerations

Citation

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

The Jackson Laboratory's Genotype Promise

Terms Of Use

Licensing Information

Also Known As:Sos1^E846K

Sos1^tm1.2Rak

Allele Symbol: Sos1^tm1.2Rak

Genotype: Sos1^tm1.2Rak/Sos1^tm1.2Rak
involves: 129S/Sv * C57BL/6 * FVB/N * SJL

Genotype: Sos1^tm1.2Rak/Sos1⁺
involves: 129S/Sv * C57BL/6 * FVB/N * SJL

Additional - Sos1^tm1.2Rak related