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Phenotypes Associated with This Genotype
Genotype
MGI:2655642
Allelic
Composition
Atp2a2tm1Ges/Atp2a2+
Genetic
Background
involves: 129X1/SvJ * Black Swiss
Find Mice Using the International Mouse Strain Resource (IMSR)
Mouse lines carrying:
Atp2a2tm1Ges mutation (1 available); any Atp2a2 mutation (23 available)
phenotype observed in females
phenotype observed in males
N normal phenotype
mortality/aging
• 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
• 2 of 16 aging heterozygotes died of unknown causes; one exhibited a prolapsed penis
• 14 of 16 aging heterozygotes with overt disease symptoms showed a sharp decline in survival between 53-81 wks of age

cardiovascular system
• 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
• 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
• after pressure overload, failing heterozygotes show a significant increase in LV chamber dilation relative to coarcted wild-type mice
• after pressure overload, failing heterozygotes show a a significant increase in LV posterior wall thickness relative to coarcted wild-type mice
• at age 53-81 weeks, some diseased heterozygotes displayed mild cardiac fibrosis, with no major cardiac lesions or hypertrophy (J:69754)
• after 10 wks of pressure overload, coarcted wild-type hearts show mild perivascular fibrosis whereas coarcted heterozygous mutant hearts exhibit moderate multifocal fibrosis (J:95608)
• 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 (J:52186)
• 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 (J:66006)
• 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 (J:95608)
• 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 (J:52186)
• 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 (J:95608)
• 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)
• after 10 wks of pressure overload, LV end-diastolic pressure is significantly elevated in coarcted failing heterozygotes relative to coarcted wild-type mice
• 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
• 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
• after 10 wk of pressure overload, ~64% of coarcted heterozygotes are in heart failure compared with 0% of coarcted wild-type mice

homeostasis/metabolism
• 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
• 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
• 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 (J:52186)
• however, no signifiant differences in the Ca2+ dependence of Ca2+ uptake activity are observed (J:52186)
• 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 (J:66006)
• however, the rate of Ca2+ transient decline (tau) is not altered significantly, suggesting no change in the rate of Ca2+ removal from the cytosol (J:66006)

muscle
• 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
• 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 (J:52186)
• 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 (J:66006)
• 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 (J:95608)
• 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 (J:52186)
• 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 (J:95608)

respiratory system
• 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

behavior/neurological
• aging heterozygotes with squamous cell tumors were lethargic

digestive/alimentary system
• aging heterozygotes frequently displayed hyperplastic changes in the epithelial lining of the esophagus, even in the absence of overt esophageal tumors
• aging heterozygotes frequently displayed hyperplastic changes in the epithelial lining of the forestomach, even in the absence of overt stomach tumors
• 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
• 3 of 10 aging heterozygotes showed squamous cell papillomas of the tongue

growth/size/body
• aging heterozygotes with squamous cell tumors exhibited wasting

integument
• 2 of 14 diseased heterozygotes showed extreme hyperkeratosis of a toenail, and another heterozygote had a large keratinized cyst bordered by squamous epithelium
• 6 of 14 heterozygotes displayed hyperkeratinized squamous cell carcinomas of the forestomach
• 1 of 14 aging heterozygotes displayed a squamous cell papilloma of the penis

renal/urinary system
• aging heterozygotes with squamous cell tumors displayed penile prolapse

reproductive system
• aging heterozygotes with squamous cell tumors displayed penile prolapse

neoplasm
• 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
• 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
• 3 of 10 aging heterozygotes showed squamous cell papillomas of the tongue
• 1 of 14 aging heterozygotes displayed a squamous cell papilloma of the penis
• 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
• 10/14 (71%) of heterozygotes had squamous cell tumors of the forestomach (non-glandular mucosa) and esophagus
• 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)
• 5/14 of heterozygotes had squamous cell tumors of the skin (2 face carcinomas, 2 penis carcinomas and 1 penis papilloma)
• 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

Mouse Models of Human Disease
DO ID OMIM ID(s) Ref(s)
keratosis follicularis DOID:2734 OMIM:124200
J:69754


Contributing Projects:
Mouse Genome Database (MGD), Gene Expression Database (GXD), Mouse Models of Human Cancer database (MMHCdb) (formerly Mouse Tumor Biology (MTB), Gene Ontology (GO)
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last database update
11/12/2019
MGI 6.14
The Jackson Laboratory