Overview

Mice heterozygous for a null Atp2a2 or SERCA2 allele exhibit a reduction in cardiac contractility, reduced blood pressure and squamous cell tumors of keratinized epithelial tissues (90% in aged mice). Homozygous embryos do not survive. This strain may be useful for studying heart disease and Darier-White disease (keratosis follicularis).

Donating Investigator

Gary E Shull, University of Cincinnati

Genetic overview

Genetic Background	Generation

Atp2a2^tm1Ges

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	Atp2a2	ATPase, Ca++ transporting, cardiac muscle, slow twitch 2

View Genetics

Research Applications

Cell Biology Research
Cardiovascular Research
Developmental Biology Research
Cancer Research

View All Research Applications

Details

Detailed Description

Atp2a2 or SERCA2 (Ca++ transporting ATPase, cardiac muscle, slow twitch 2) encodes an intracellular pump located in the sarcoplasmic or endoplasmic reticula of muscle cells. This ATPase is involved in the cardiac contraction/relaxation cycle and in calcium translocation. Mutations in ATP2A2 are associated with Darier-White disease (keratosis follicularis). Mice heterozygous for this allele are viable and fertile. Homozygous embryos do not survive. Heterozygotes exhibit a reduction in cardiac contractility, reduced blood preesure, susceptibility to cardiac disease in response to
pressure overload, and a reduced force-frequency response in heart. Approximately 90% of aging (50+ weeks) heterozygotes develop squamous cell tumors of keratinized epithelial tissues (including stomach, esophagus, tongue, oral mucosa, and skin). This strain may be useful for studying heart disease and Darier-White disease.

Development

A targeting vector containing the neomycin resistance and herpes simplex virus thymidine kinase genes was used to disrupt part of the promoter, the transcription initiation site and exons 1, 2 and part of 3. The construct was electroporated into 129X1/SvJ-derived embryonic stem (ES) cells. Correctly targeted ES cells were injected into blastocysts. The resulting chimeric animals were crossed to Black Swiss mice. Mice from the colony were backcrossed to FVB/N for at least 10 generations. Upon arrival, mice were bred to FVB/NJ for at least 1 generation to establish the colony.

Control Suggestions

Wild-type from the colony
001800 FVB/NJ

Additional Information

Considerations for Choosing Controls

Selected References

Periasamy M; Reed TD; Liu LH; Ji Y; Loukianov E; Paul RJ; Nieman ML ; Riddle T ; Duffy JJ ; Doetschman T ; Lorenz JN ; Shull GE. 1999. Impaired cardiac performance in heterozygous mice with a null mutation in the sarco(endo)plasmic reticulum Ca2+-ATPase isoform 2 (SERCA2) gene. J Biol Chem 274(4):2556-62PubMed: 9891028 MGI: J:52186

View All References

Genetics

Atp2a2^tm1Ges

Allele Symbol: Atp2a2^tm1Ges

Allele Name	targeted mutation 1, Gary E Shull
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	SERCA2a knockout; SERCA2a^-
Gene Symbol and Name	Atp2a2, ATPase, Ca++ transporting, cardiac muscle, slow twitch 2
Gene Synonym(s)
Strain of Origin	129X1/SvJ
Chromosome	5
Molecular Note	A genomic fragment containing the promoter, transcription initiation site, the first two exons and part of the third exon was replaced with a neomycin selection cassette.

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).

keratosis follicularis

Research Areas By Phenotype

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

Cell Biology Research
- Channel and Transporter Defects
  - calcium
Cardiovascular Research
- Heart Abnormalities
  - cardiomyopathy
Developmental Biology Research
- Embryonic Lethality (Homozygous)
Cancer Research
- Increased Tumor Incidence
  - Skin Cancers

Mammalian Phenotype Terms by Genotype

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

Genotype: Atp2a2^tm1Ges/Atp2a2^tm1Ges
involves: 129X1/SvJ * Black Swiss

mortality/aging

prenatal lethality, complete penetrance
- homozygotes are embryonic lethal; however, stage of lethality is not specified

Genotype: Atp2a2^tm1Ges/Atp2a2⁺
involves: 129X1/SvJ * Black Swiss

behavior/neurological phenotype

lethargy
- aging heterozygotes with squamous cell tumors were lethargic

cardiovascular system phenotype

abnormal cardiac muscle relaxation
- after 10 wks of pressure overload, a portion of coarcted heterozygotes show significant diastolic cardiac dysfunction i.e. reduced rate of relaxation (-dP/dt) relative to coarcted wild-type mice
- male heterozygotes exhibit a significant reduction in the absolute value of negative dP/dt (dP/dtmin) relative to wild-type males under non-stimulated conditions and at all levels of beta-adrenergic stimulation

cardiac fibrosis
- after 10 wks of pressure overload, coarcted wild-type hearts show mild perivascular fibrosis whereas coarcted heterozygous mutant hearts exhibit moderate multifocal fibrosis
- at age 53-81 weeks, some diseased heterozygotes displayed mild cardiac fibrosis, with no major cardiac lesions or hypertrophy

cardiac hypertrophy
- after 10 wks of pressure overload, coarcted wild-type hearts exhibit mild cardiomyocyte hypertrophy whereas coarcted heterozygous mutant hearts show diffuse, moderate myocyte hypertrophy
- coarcted failing heterozygotes exhibit an eccentric, dilated form of cardiac hypertrophy whereas coarcted wild-type mice and nonfailing heterozygotes show a concentric form of hypertrophy

congestive heart failure
- after 10 wk of pressure overload, ~64% of coarcted heterozygotes are in heart failure compared with 0% of coarcted wild-type mice

decreased left ventricle systolic pressure
- )
- male heterozygotes exhibit a significantly lower LV systolic pressure than wild-type males under non-stimulated conditions and at low doses of dobutamine (1-2 ng/min/g of body weight), but not at higher levels of beta-adrenergic stimulation (4-32 ng/min/g)

decreased systemic arterial blood pressure
- ergic stimulation (4-32 ng/min/g)
- heterozygotes are viable and healthy, with no cardiac hypertrophy or overt signs of a disease phenotype
- however, 12-14-week-old male heterozygotes exhibit a significantly lower mean arterial blood pressure than wild-type males under non-stimulated conditions and at low doses of dobutamine (1-2 ng/min/g of body weight), but not at higher levels of beta-adrenergic stimulation (4-32 ng/min/g)
- no significant differences are noted in mean heart rate under non-stimulated conditions or at low doses of dobutamine

decreased ventricle muscle contractility
- after 10 wks of pressure overload, a portion of coarcted heterozygotes show significant systolic cardiac dysfunction i.e. reduced rate of contraction (+dP/dt) relative to coarcted wild-type mice
- left ventricular cardiomyocytes isolated from adult heterozygotes and paced at 0.25 Hz display a ~30% decrease in the percentage of cell shortening as well as a ~40% reduction in the rate of cell shortening and cell relengthening
- male heterozygotes exhibit a significant reduction in the absolute value of positive dP/dt (dP/dtmax) relative to wild-type males under non-stimulated conditions and at all levels of beta-adrenergic stimulation

dilated heart left ventricle
- after pressure overload, failing heterozygotes show a significant increase in LV chamber dilation relative to coarcted wild-type mice

heart left ventricle hypertrophy
- after pressure overload, failing heterozygotes show a significantly greater increase in LV mass and LV hypertrophy relative to coarcted wild-type mice at 5 and 10 wks of aortic coarctation

increased left ventricle diastolic pressure
- after 10 wks of pressure overload, LV end-diastolic pressure is significantly elevated in coarcted failing heterozygotes relative to coarcted wild-type mice

increased response of heart to induced stress
- after pressure overload, exhibit an eccentric dilated form of cardiac hypertrophy instead of the concentric form of hypertrophy seen in wild-type controls, and show a greater increase in cardiac fibrosis, left ventricle hypertrophy, dilation, posterior wall thickness, and end-diastolic pressure, and reduced contraction and relaxation rates, resulting in heart failure that is not observed in wild-type
- ll thickness, and end-diastolic pressure, and reduced contraction and relaxation rates, resulting in heart failure that is not observed in wild-type

thick ventricular wall
- after pressure overload, failing heterozygotes show a a significant increase in LV posterior wall thickness relative to coarcted wild-type mice

digestive/alimentary phenotype

esophageal epithelium hyperplasia
- aging heterozygotes frequently displayed hyperplastic changes in the epithelial lining of the esophagus, even in the absence of overt esophageal tumors

increased esophageal papilloma incidence
- 7 of 14 aging heterozygotes displayed squamous cell papillomas of the esophagus
- squamous cell papillomas were also observed in forestomachs, although less commonly than carcinomas

increased tongue papilloma incidence
- 3 of 10 aging heterozygotes showed squamous cell papillomas of the tongue

stomach epithelial hyperplasia
- aging heterozygotes frequently displayed hyperplastic changes in the epithelial lining of the forestomach, even in the absence of overt stomach tumors

growth/size/body region phenotype

cachexia
- aging heterozygotes with squamous cell tumors exhibited wasting

cardiac hypertrophy
- after 10 wks of pressure overload, coarcted wild-type hearts exhibit mild cardiomyocyte hypertrophy whereas coarcted heterozygous mutant hearts show diffuse, moderate myocyte hypertrophy
- coarcted failing heterozygotes exhibit an eccentric, dilated form of cardiac hypertrophy whereas coarcted wild-type mice and nonfailing heterozygotes show a concentric form of hypertrophy

heart left ventricle hypertrophy
- after pressure overload, failing heterozygotes show a significantly greater increase in LV mass and LV hypertrophy relative to coarcted wild-type mice at 5 and 10 wks of aortic coarctation

homeostasis/metabolism phenotype

abnormal calcium ion homeostasis
- cardiac homogenates from 15-16-week-old heterozygotes show a ~33% reduction in the maximum velocity of Ca²⁺ uptake by sarcoplasmic reticulum relative to wild-type homogenates
- however, no signifiant differences in the Ca²⁺ dependence of Ca²⁺ uptake activity are observed
- however, the rate of Ca²⁺ transient decline (tau) is not altered significantly, suggesting no change in the rate of Ca²⁺ removal from the cytosol
- left ventricular cardiomyocytes isolated from adult heterozygotes and paced at 0.25 Hz show a ~40-60% and a ~30-40% reduction in SR Ca²⁺ stores and Ca²⁺ release, respectively

increased response of heart to induced stress
- after pressure overload, exhibit an eccentric dilated form of cardiac hypertrophy instead of the concentric form of hypertrophy seen in wild-type controls, and show a greater increase in cardiac fibrosis, left ventricle hypertrophy, dilation, posterior wall thickness, and end-diastolic pressure, and reduced contraction and relaxation rates, resulting in heart failure that is not observed in wild-type
- ll thickness, and end-diastolic pressure, and reduced contraction and relaxation rates, resulting in heart failure that is not observed in wild-type

pulmonary edema
- after 10 wk of pressure overload, 64% of coarcted heterozygotes exhibit pulmonary edema (i.e. a significantly increased wet lung weight-to-body weight ratio) relative to 0% of coarcted wild-type mice

integument phenotype

hyperkeratosis
- 6 of 14 heterozygotes displayed hyperkeratinized squamous cell carcinomas of the forestomach

increased skin papilloma incidence
- 1 of 14 aging heterozygotes displayed a squamous cell papilloma of the penis

toenail hyperkeratosis
- 2 of 14 diseased heterozygotes showed extreme hyperkeratosis of a toenail, and another heterozygote had a large keratinized cyst bordered by squamous epithelium

mortality/aging

increased sensitivity to induced morbidity/mortality
- when subjected to aortic coarctation at 10-12 wks of age, 4 of 11 heterozygotes die of heart failure between 4 and 8 wks of pressure overload whereas no mortality is observed in wild-type mice

premature death
- 14 of 16 aging heterozygotes with overt disease symptoms showed a sharp decline in survival between 53-81 wks of age
- 2 of 16 aging heterozygotes died of unknown causes; one exhibited a prolapsed penis

muscle phenotype

abnormal cardiac muscle relaxation
- after 10 wks of pressure overload, a portion of coarcted heterozygotes show significant diastolic cardiac dysfunction i.e. reduced rate of relaxation (-dP/dt) relative to coarcted wild-type mice
- male heterozygotes exhibit a significant reduction in the absolute value of negative dP/dt (dP/dtmin) relative to wild-type males under non-stimulated conditions and at all levels of beta-adrenergic stimulation

decreased ventricle muscle contractility
- after 10 wks of pressure overload, a portion of coarcted heterozygotes show significant systolic cardiac dysfunction i.e. reduced rate of contraction (+dP/dt) relative to coarcted wild-type mice
- left ventricular cardiomyocytes isolated from adult heterozygotes and paced at 0.25 Hz display a ~30% decrease in the percentage of cell shortening as well as a ~40% reduction in the rate of cell shortening and cell relengthening
- male heterozygotes exhibit a significant reduction in the absolute value of positive dP/dt (dP/dtmax) relative to wild-type males under non-stimulated conditions and at all levels of beta-adrenergic stimulation

heart left ventricle hypertrophy
- after pressure overload, failing heterozygotes show a significantly greater increase in LV mass and LV hypertrophy relative to coarcted wild-type mice at 5 and 10 wks of aortic coarctation

neoplasm

increased esophageal papilloma incidence
- 7 of 14 aging heterozygotes displayed squamous cell papillomas of the esophagus
- squamous cell papillomas were also observed in forestomachs, although less commonly than carcinomas

increased skin papilloma incidence
- 1 of 14 aging heterozygotes displayed a squamous cell papilloma of the penis

increased squamous cell carcinoma incidence
- 10/14 (71%) of heterozygotes had squamous cell tumors of the forestomach (non-glandular mucosa) and esophagus
- 5/14 of heterozygotes had squamous cell tumors of the skin (2 face carcinomas, 2 penis carcinomas and 1 penis papilloma)
- 9 of 10 of heterozygotes had squamous cell tumors in the tongue or oral mucosa (4 tongue carcinomas, 3 tongue papillomas and 2 oral mucosa (cheek) carcinomas)
- additional squamous cell tumors were observed in retired heterozygous breeders, including carcinomas of the esophagus, lip, palette, and the skin adjacent to the vagina, penis, and anus
- at age 53-81 weeks, 13 of 14 (93%) of heterozygotes had hyperkeratinized squamous cell tumors of the stomach, esophagus, tongue, oral mucosa, and skin, with an average of more than two tumors per mouse

increased tongue papilloma incidence
- 3 of 10 aging heterozygotes showed squamous cell papillomas of the tongue

increased tumor incidence
- aging heterozygotes (53-81 weeks of age) exhibited a high predisposition to squamous cell tumor formation, with 30 squamous cell tumors noted among 14 heterozygotes vs none in wild-type controls

renal/urinary system phenotype

penis prolapse
- aging heterozygotes with squamous cell tumors displayed penile prolapse

reproductive system phenotype

penis prolapse
- aging heterozygotes with squamous cell tumors displayed penile prolapse

respiratory system phenotype

pulmonary edema
- after 10 wk of pressure overload, 64% of coarcted heterozygotes exhibit pulmonary edema (i.e. a significantly increased wet lung weight-to-body weight ratio) relative to 0% of coarcted wild-type mice

Genotype: Atp2a2^tm1Ges/Atp2a2⁺
involves: 129X1/SvJ

cellular phenotype

abnormal osteoclast differentiation
- Normal - however, osteoclast differentiation is rescued by retroviral expression of CREB1
- impaired

hematopoietic system phenotype

abnormal osteoclast differentiation
- Normal - however, osteoclast differentiation is rescued by retroviral expression of CREB1
- impaired

immune system phenotype

abnormal osteoclast differentiation
- Normal - however, osteoclast differentiation is rescued by retroviral expression of CREB1
- impaired

skeleton phenotype

abnormal osteoclast differentiation
- Normal - however, osteoclast differentiation is rescued by retroviral expression of CREB1
- impaired

References

Periasamy M; Reed TD; Liu LH; Ji Y; Loukianov E; Paul RJ; Nieman ML ; Riddle T ; Duffy JJ ; Doetschman T ; Lorenz JN ; Shull GE. 1999. Impaired cardiac performance in heterozygous mice with a null mutation in the sarco(endo)plasmic reticulum Ca2+-ATPase isoform 2 (SERCA2) gene. J Biol Chem 274(4):2556-62PubMed: 9891028 MGI: J:52186

Additional - Atp2a2^tm1Ges related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Standard PCR:Atp2a2
- Standard PCR:Generic Neo
- Probe:Generic Neo
- Genotyping resources and troubleshooting
Breeding Considerations

While maintaining a live colony, these mice are bred as heterozygotes. Mice homozygous for the mutation are not viable.
- Additional Breeding and Husbandry Support
Citation
When using the FVB.129X1(Cg)-Atp2a2^tm1Ges/Mmjax mouse strain in a publication, please cite the originating article(s) and include MMRRC stock #36806 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

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

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Donating Investigator

Genetic overview

Research Applications

Detailed Description

Development

Control Suggestions

Additional Information

Selected References

Atp2a2tm1Ges

Allele Symbol: Atp2a2tm1Ges

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: Atp2a2tm1Ges/Atp2a2tm1Gesinvolves: 129X1/SvJ * Black Swiss

mortality/aging

Genotype: Atp2a2tm1Ges/Atp2a2+involves: 129X1/SvJ * Black Swiss

behavior/neurological phenotype

cardiovascular system phenotype

digestive/alimentary phenotype

growth/size/body region phenotype

homeostasis/metabolism phenotype

integument phenotype

mortality/aging

muscle phenotype

neoplasm

renal/urinary system phenotype

reproductive system phenotype

respiratory system phenotype

Genotype: Atp2a2tm1Ges/Atp2a2+involves: 129X1/SvJ

cellular phenotype

hematopoietic system phenotype

immune system phenotype

skeleton phenotype

References

Additional - Atp2a2tm1Ges 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

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Atp2a2^tm1Ges

Allele Symbol: Atp2a2^tm1Ges

Genotype: Atp2a2^tm1Ges/Atp2a2^tm1Ges
involves: 129X1/SvJ * Black Swiss

Genotype: Atp2a2^tm1Ges/Atp2a2⁺
involves: 129X1/SvJ * Black Swiss

Genotype: Atp2a2^tm1Ges/Atp2a2⁺
involves: 129X1/SvJ

Additional - Atp2a2^tm1Ges related