Overview

Also Known As:Noonan Syndrome with Multiple Lentigines knock-in (NSML/+ or Ptpn11^Y279C/+; formerly called Leopard syndrome knock-in [LS/+])

Mice heterozygous for the NSML knock-in allele (NSML/+ or Ptpn11^Y279C/+; formerly called LS/+) have the Ptpn11*Y279C mutation in exon 7 that is one of the two most common mutations associated with Noonan Syndrome with Multiple Lentigines (NSML; formerly called Leopard syndrome [LS]). These mice recapitulate several characteristics of the human disorder, including hypertrophic cardiomyopathy, short stature, craniofacial dysmorphia, abnormal genitalia and substantial macrophage accumulation in the organ of Corti.

Donating Investigator

Maria I Kontaridis, Beth Israel Deaconess Medical Center

Genetic overview

Genetic Background	Generation

Ptpn11^tm4.2Bgn

Allele Type	Gene Symbol	Gene Name
Targeted (Humanized sequence)	Ptpn11	protein tyrosine phosphatase, non-receptor type 11

View Genetics

Research Applications

Cancer Research
Research Tools
Cell Biology Research
Developmental Biology Research
Internal/Organ Research
Cardiovascular Research
Neurobiology Research
Sensorineural Research

View All Research Applications

Base Price

Starting at:

$2,854.50 Domestic price Cryo Recovery

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Details

Detailed Description

Noonan Syndrome with Multiple Lentigines (NSML; formerly called Leopard syndrome [LS]) is an autosomal dominant "RASopathy" characterized by multiple brown skin spots (lentigines), congenital heart disease, short stature, genital abnormalities, hearing loss and distinctive facial features. In humans, the PTPN11*Y279C mutation is one of the two most common NSML mutations.

The ubiquitously expressing (non-inducible) NSML knock-in allele (Ptpn11^Y279C) encodes the Ptpn11*Y279C mutant protein. Mice heterozygous for this allele (Ptpn11^Y279C/+ or NSML/+; formerly LS/+) recapitulate several characteristics of the human disorder. Morphologic, histologic, echocardiographic, and molecular evidence of hypertrophic cardiomyopathy is evident by 12 weeks of age.

NSML/+ mice may also exhibit any of the following at variable penetrance: craniofacial dysmorphia, skeletal/chest abnormalities, shorter stature compared to wildtype mice. Heterozygous mice exhibit premature lethality (~25% die between 8-12 months of age), and surviving NSML/+ mice of both sexes are viable and fertile to at least 12 months of age.

In addition, heterozygotes have abnormal genitalia and substantial macrophage accumulation in the organ of Corti (inner ear). Importantly, treatment with the mTOR-inhibitor rapamycin effectively reverses the NSML disease phenotype.

Specifically, NSML/+ mice have hypertelorism appearance (abnormal faces, with distinctly smaller, more slanted eyes and a planar nasal bridge). Heart and/or cardiomyocyte lysates from NSML/+ mice show enhanced binding of Shp2 to Irs1, decreased Shp2 catalytic activity, and abrogated agonist-evoked Erk/Mapk signaling. NSML/+ mice also exhibited increased basal and agonist-induced Akt and mTor activity. The donating investigator reports they keep breeding units between 4-8 months of age, and abnormal genitalia can sometimes delay breeding by heterozygous males.

Expression of this Ptpn11^Y279C knock-in allele (both mRNA and protein) is at levels comparable to wildtype Ptpn11. Peripheral blood, bone marrow, spleen, and thymus from NSML/+ mice show no apparent abnormalities in any hematological parameter.

The donating investigator reports that homozygous mice (Ptpn11^Y279C/Y279C or NSML/NSML; formerly LS/LS) exhibit a more severe phenotype and ~50% of homozygotes mice die between 8-12 months of age. Homozygous mice are born at significantly reduced frequency, and homozygous females do not lactate.

Development

The Ptpn11^Y279C knock-in allele has the Ptpn11*Y279C mutation in exon 7 that is one of the two most common mutations associated with Noonan Syndrome with Multiple Lentigines (NSML; formerly called Leopard syndrome [LS]). This knock-in allele was created by Dr. Maria I. Kontaridis (Beth Israel Deaconess Medical Center). First, the inducible NSML ("iLS") targeting vector was designed to modify the protein tyrosine phosphatase, non-receptor type 11 gene (Ptpn11 or Shp2) on chromosome 5 with (from 5prime to 3prime) a loxP site upstream of endogenous exon 7, a loxP511 site, an inverted Y279C mutant exon 7 (encoding an amino acid substitution of cysteine for tyrosine at position 279), an inverted loxP site, an inverted loxP511 site, a frt-flanked neo cassette. This also inserted two HpyCH4 restriction sites (intended to be useful in screening/genotyping): one in the mutant exon 7 Y279C site and the other at the 5prime end of the inserted targeted mutant sequence 35 bp downstream of the 5prime loxP511 site. The construct was electroporated into 129S6/SvEvTac-derived TC1 embryonic stem (ES) cells.
Chimeric mice were bred to C57BL/6J for germline transmission. The resulting iLS/+ mice (129S6/SvEv x C57BL6/J) were crossed to Flp recombinase-expressing mice on a C57BL/6J genetic background (Stock No. 005703) to excise the frt-flanked neo cassette. Next, the mice were bred to Cre recombinase-expressing mice on a C57BL/6J genetic background (Stock No. 003724) to remove the floxed endogenous exon 7 and place the Y279C mutant exon 7 into transcriptional orientation; resulting in the ubiquitously expressing (non-inducible) NSML allele ("LS"). The FLP and Cre transgenes were selectively removed in future breedings.
Heterozygous mice (Ptpn11^Y279C/+ or NSML/+; formerly LS/+) were bred with wildtype C57BL/6J mice for at least nine generations prior to sending black male mice in 2014 to Frederick National Laboratory for Cancer Research (Leidos Biomedical Research, Inc.). There, the NSML/+ mice were bred with C57BL/6J females at least one generation. In 2015, black male mice were then sent to The Jackson Laboratory Repository. Upon arrival, sperm was cryopreserved. To generate the living NSML colony, an aliquot of the frozen sperm was used to fertilize oocytes from C57BL/6J female mice (Stock No. 000664). The NSML colony was then maintained by breeding heterozygous mice to wildtype mice from the colony or with C57BL/6J inbred mice.

Control Suggestions

Wild-type from the colony

Approximate Controls

000664 C57BL/6J

Additional Information

Considerations for Choosing Controls

Selected References

Marin TM; Keith K; Davies B; Conner DA; Guha P; Kalaitzidis D; Wu X; Lauriol J; Wang B; Bauer M; Bronson R; Franchini KG; Neel BG; Kontaridis MI. 2011. Rapamycin reverses hypertrophic cardiomyopathy in a mouse model of LEOPARD syndrome-associated PTPN11 mutation. J Clin Invest 121(3):1026-43PubMed: 21339643 MGI: J:172033

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Genetics

Ptpn11^tm4.2Bgn

Allele Symbol: Ptpn11^tm4.2Bgn

Allele Name	targeted mutation 4.2, Benjamin G Neel
Allele Type	Targeted (Humanized sequence)
Allele Synonym(s)	Ptpn11^LS; Ptpn11^Y279C
Gene Symbol and Name	Ptpn11, protein tyrosine phosphatase, non-receptor type 11
Gene Synonym(s)
Strain of Origin	129S6/SvEvTac
Chromosome	5
Molecular Note	A loxP site was inserted upstream of exon 7. An inverted modified exon 7 with a nucleotide substitutions that result in the amino acid substitution of cysteine for tyrosine at position 279 (Y279C) with a 5' loxP site was flanked by loxP511 sites and inserted downstream of exon 7 along with an FRT flanked neo cassette. Flp-mediated recombination removed the neo cassette, and cre-mediated recombination removed the endogenous exon 7 and reverted the orientation of the modified exon 7. The amino acid substitution is one of the two most common mutations in Leopard syndrome.

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 with multiple lentigines

Research Areas By Phenotype

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

Cancer Research
- Oncogenes
- Genes Regulating Growth and Proliferation
Research Tools
- Reproductive Biology Research
- Cardiovascular Research
- Cancer Research
Cell Biology Research
- Transcriptional Regulation
- Genes Regulating Growth and Proliferation
- Signal Transduction
Developmental Biology Research
- Craniofacial and Palate Defects
- Internal/Organ Defects
  - heart
  - urogenital
- Postnatal Lethality
Internal/Organ Research
- Heart Abnormalities
Cardiovascular Research
- Heart Abnormalities
  - cardiomyopathy
Neurobiology Research
- Hearing Defects
Sensorineural Research
- Hearing Defects

Mammalian Phenotype Terms by Genotype

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

Genotype: Ptpn11^tm4.2Bgn/Ptpn11⁺
involves: 129S6/SvEvTac * C57BL/6J * FVB/N

cardiovascular system phenotype

cardiac fibrosis
- in older mice

cardiac hypertrophy
- with enlarged nuclei, myofiber disarray, and inflammatory cell accumulation in interstitial fiber

decreased ventricle muscle contractility
- at 52 weeks

dilated cardiomyopathy
- by 52 weeks, with increased diastolic dimension and thinning of the posterior walls
- Normal - however, treatment with rapamycin normalizes hypertrophic cardiomyopathy

enlarged heart
- by 12 weeks

enlarged myocardial fiber
- adult cardiomyocytes exhibit enlarged area and increased cell width compared to in wild-type mice
- Normal - however, rapamycin treatment rescues cardiomyocyte size

heart left ventricle hypertrophy
- by 12 weeks

increased heart weight
- at 12 and 16 weeks
- Normal - however, treatment with rapamycin rescues heart weight

thick interventricular septum
- at 16 weeks

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

craniofacial phenotype

abnormal cranium size
- mice exhibit increased skull width-to-length ratio compared with wild-type mice

abnormal facial morphology
- with smaller, more slanted eyes and a planar nasal bridge

depressed nasal bridge
- planar nasal bridge

growth/size/body region phenotype

abnormal chest morphology
- with pectus carinatum superiorly and pectus excavatum inferiorly

abnormal facial morphology
- with smaller, more slanted eyes and a planar nasal bridge

cardiac hypertrophy
- with enlarged nuclei, myofiber disarray, and inflammatory cell accumulation in interstitial fiber

decreased body size
- by weaning

depressed nasal bridge
- planar nasal bridge

enlarged heart
- by 12 weeks

heart left ventricle hypertrophy
- by 12 weeks

increased heart weight
- at 12 and 16 weeks
- Normal - however, treatment with rapamycin rescues heart weight

hearing/vestibular/ear phenotype

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

limbs/digits/tail phenotype

short femur

mammalian phenotype

cardiovascular system phenotype
- Normal - mice exhibit normal valvular development and no septal defects

hematopoietic system phenotype
- Normal - mice exhibit normal hematological parameters

mortality/aging

premature death
- by 52 weeks, more mice die than wild-type mice

muscle phenotype

decreased ventricle muscle contractility
- at 52 weeks

dilated cardiomyopathy
- by 52 weeks, with increased diastolic dimension and thinning of the posterior walls
- Normal - however, treatment with rapamycin normalizes hypertrophic cardiomyopathy

enlarged myocardial fiber
- adult cardiomyocytes exhibit enlarged area and increased cell width compared to in wild-type mice
- Normal - however, rapamycin treatment rescues cardiomyocyte size

heart left ventricle hypertrophy
- by 12 weeks

reproductive system phenotype

abnormal reproductive system morphology
- mice exhibit abnormal genitals compared with wild-type mice

skeleton phenotype

abnormal cranium size
- mice exhibit increased skull width-to-length ratio compared with wild-type mice

short femur

vision/eye phenotype

abnormal eye distance/ position
- smaller, more slanted eyes

ocular hypertelorism
- with normal inner canthal distance

References

Marin TM; Keith K; Davies B; Conner DA; Guha P; Kalaitzidis D; Wu X; Lauriol J; Wang B; Bauer M; Bronson R; Franchini KG; Neel BG; Kontaridis MI. 2011. Rapamycin reverses hypertrophic cardiomyopathy in a mouse model of LEOPARD syndrome-associated PTPN11 mutation. J Clin Invest 121(3):1026-43PubMed: 21339643 MGI: J:172033

Additional - Ptpn11^tm4.2Bgn related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Standard PCR:Ptpn11 Alternate2
- Genotyping resources and troubleshooting
Breeding Considerations

When maintaining our live colony, heterozygous females are bred to wildtype males from the colony or with C57BL/6J inbred males (Stock No. 000664).

Heterozygous mice (both female and male) are viable and fertile to at least 12 months of age. ~25% of heterozygotes die between 8-12 months of age. The donating investigator reports they keep breeding units between 4-8 months of age, and abnormal genitalia can sometimes delay breeding by heterozygous males. Homozygous mice exhibit a more severe phenotype; ~50% die between 8-12 months of age and females do not lactate. Homozygotes are born at significantly reduced frequency.
- Additional Breeding and Husbandry Support
Citation
When using the Noonan Syndrome with Multiple Lentigines knock-in (NSML/+ or Ptpn11^Y279C/+; formerly called Leopard syndrome knock-in [LS/+]) mouse strain in a publication, please cite the originating article(s) and include JAX stock #026759 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

Pricing & Availability

Cryo Recovery

Domestic
International

Live Mouse

Age

Genotype

Price

weeks

Cryorecovery - Pricing

Service/Product	Description	Price
	Heterozygous or wildtype for Ptpn11<tm4.2Bgn>

Related Products and Services

Frozen Mouse Embryo	B6.129S6(Cg)-Ptpn11<tm4.2Bgn>/FcrJ	$2595.00
Frozen Mouse Embryo	B6.129S6(Cg)-Ptpn11<tm4.2Bgn>/FcrJ	$2595.00
Frozen Mouse Embryo	B6.129S6(Cg)-Ptpn11<tm4.2Bgn>/FcrJ	$3373.50
Frozen Mouse Embryo	B6.129S6(Cg)-Ptpn11<tm4.2Bgn>/FcrJ	$3373.50

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Also Known As:Noonan Syndrome with Multiple Lentigines knock-in (NSML/+ or Ptpn11Y279C/+; formerly called Leopard syndrome knock-in [LS/+])

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Approximate Controls

Additional Information

Selected References

Ptpn11tm4.2Bgn

Allele Symbol: Ptpn11tm4.2Bgn

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: Ptpn11tm4.2Bgn/Ptpn11+involves: 129S6/SvEvTac * C57BL/6J * FVB/N

cardiovascular system phenotype

craniofacial phenotype

growth/size/body region phenotype

hearing/vestibular/ear phenotype

limbs/digits/tail phenotype

mammalian phenotype

mortality/aging

muscle phenotype

reproductive system phenotype

skeleton phenotype

vision/eye phenotype

References

Additional - Ptpn11tm4.2Bgn related

Genotyping Protocols

Breeding Considerations

Citation

Animal Health Reports

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

Live Mouse

Cryorecovery - Pricing

Related Products and Services

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms Of Use

Additional Use Restrictions Apply

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Also Known As:Noonan Syndrome with Multiple Lentigines knock-in (NSML/+ or Ptpn11^Y279C/+; formerly called Leopard syndrome knock-in [LS/+])

Ptpn11^tm4.2Bgn

Allele Symbol: Ptpn11^tm4.2Bgn

Genotype: Ptpn11^tm4.2Bgn/Ptpn11⁺
involves: 129S6/SvEvTac * C57BL/6J * FVB/N

Additional - Ptpn11^tm4.2Bgn related