Phenotypes Associated with This Genotype

Genotype
MGI:2655642

• Allelic Composition: Atp2a2^tm1Ges/Atp2a2⁺
• Genetic Background: involves: 129X1/SvJ * Black Swiss

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

mortality/aging

increased susceptibility to induced morbidity/mortality ( J:95608 )

• 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 ( J:69754 )

• 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

cardiac hypertrophy ( J:95608 )

• 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 ( J:95608 )

• 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 heart left ventricle posterior wall thickness ( J:95608 )

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

dilated heart left ventricle ( J:95608 )

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

cardiac fibrosis ( J:69754 , J:95608 )

• 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)

decreased ventricle muscle contractility ( J:52186 , J:66006 , 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)

abnormal cardiac muscle relaxation ( J:52186 , 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)

decreased left ventricle systolic pressure ( J:52186 )

• 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)

increased left ventricle diastolic pressure ( J:95608 )

• 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 ( J:95608 )

• 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

decreased systemic arterial blood pressure ( J:52186 )

• 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

congestive heart failure ( J:95608 )

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

homeostasis/metabolism

increased response of heart to induced stress ( J:95608 )

• 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

pulmonary edema ( J:95608 )

• 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

abnormal calcium ion homeostasis ( J:52186 , J:66006 )

• 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

heart left ventricle hypertrophy ( J:95608 )

• 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

decreased ventricle muscle contractility ( J:52186 , J:66006 , 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)

abnormal cardiac muscle relaxation ( J:52186 , 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

pulmonary edema ( J:95608 )

• 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

lethargy ( J:69754 )

• aging heterozygotes with squamous cell tumors were lethargic

digestive/alimentary system

esophageal epithelium hyperplasia ( J:69754 )

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

stomach epithelial hyperplasia ( J:69754 )

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

increased esophageal papilloma incidence ( J:69754 )

• 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 ( J:69754 )

• 3 of 10 aging heterozygotes showed squamous cell papillomas of the tongue

growth/size/body

cardiac hypertrophy ( J:95608 )

• 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 ( J:95608 )

• 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

cachexia ( J:69754 )

• aging heterozygotes with squamous cell tumors exhibited wasting

integument

toenail hyperkeratosis ( J:69754 )

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

hyperkeratosis ( J:69754 )

• 6 of 14 heterozygotes displayed hyperkeratinized squamous cell carcinomas of the forestomach

increased skin papilloma incidence ( J:69754 )

• 1 of 14 aging heterozygotes displayed a squamous cell papilloma of the penis

renal/urinary system

penis prolapse ( J:69754 )

♂ • aging heterozygotes with squamous cell tumors displayed penile prolapse

reproductive system

penis prolapse ( J:69754 )

♂ • aging heterozygotes with squamous cell tumors displayed penile prolapse

neoplasm

increased tumor incidence ( J:69754 )

• 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

increased esophageal papilloma incidence ( J:69754 )

• 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 ( J:69754 )

• 3 of 10 aging heterozygotes showed squamous cell papillomas of the tongue

increased skin papilloma incidence ( J:69754 )

• 1 of 14 aging heterozygotes displayed a squamous cell papilloma of the penis

increased squamous cell carcinoma incidence ( J:69754 )

• 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