Mouse Genome Informatics
cn1
    Fxntm2Mkn/Fxntm2.1Mkn
Tg(Ckmm-cre)1Lrsn/0

involves: 129 * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mutant mice die at 76 10 days (10-12 weeks) (J:75420)
• antioxidant idebenone delays death by 1 week (J:90401)

cardiovascular system
• at 7 weeks, mutant mice display normal or slightly increased iron content in cardiac mitochondria relative to wild-type mice (791 108 ng iron/mg protein vs 749 35 ng iron/mg protein, respectively) (J:75420)
• however, at 10 weeks, cardiac mitochondrial iron is significantly increased (1,049 205 ng iron/mg protein vs 579 65 ng iron/mg protein) (J:75420)
• cardiac intramitochondrial iron concentration significantly increases between 8-9 weeks to reach ~2-fold the normal iron content by death (J:90401)
• at 10 weeks, mutant mice exhibit sparse atrophied myofibrils which are pushed to the periphery, as well as disrupted myofibrils at the positions of intercalated discs (J:75420)
• earlier, at 4 weeks, mutant hearts display abnormal accumulation of lipid droplets and few degenerating fibers; by 5-6 weeks, a gradual reduction in lipid droplets, swollen mitochondria, and disorganized cardiac muscle fibers are observed (J:90401)
• by 10 weeks, mutant mice show myocardial degeneration with cytoplasmic vacuolization in myocytes, indicating necrosis
• starting at 5 weeks, mutant hearts show a significantly increased ventricular septum wall thickness
• at 7 weeks, mutant mice exhibit a progressively increasing heart to body weight ratio, reaching 18.6 5 mg/g vs 5.6 0.4 mg/g for wild-type littermates at death
• no evidence in heart size difference is noted at 2-3 weeks of age
• starting at 5 weeks, mutant hearts exhibit a significantly increased left ventricular mass (J:90401)
• starting at 5 weeks, mutant hearts display a significant increase in left ventricle diastolic and systolic diameters
• by 10 weeks, mutant mice display notable thickening of the left ventricular wall (J:75420)
• starting at 5 weeks, mutant hearts show significantly increased left ventricular posterior wall thickness (J:90401)
• by 10 weeks, mutant mice show post-necrotic fibrosis in cardiac muscle
• mutant mice display an initial cardiac hypertrophy which develops into a dilated cardiomyopathy without skeletal muscle involvement (J:75420)
• at 7 weeks, hypertrophic cardiomyopathy is rapidly associated with significant geometric remodeling (J:90401)
• antioxidant idebenone delays the cardiac disease onset, progression and death by 1 week, but fails to correct the Fe-S enzyme deficiency and has no effect on the status of lipid peroxidation (oxidative stress) (J:90401)
• at 8 weeks of age, mutant mice show a 67% reduction of resting cardiac output, associated with saturated hypertrophy
• at 5 and 7 weeks of age, mutant mice show a 24% and 66% decrease of the shortening fraction, respectively
• during tribromoethanol anesthesia, most 9-wk-old mutants display a prolonged PR interval that progresses from a first- to a third-degree (complete) atrioventricular block with severe bradycardia

cellular
• at 10 weeks, mutant mice display many disorganized mitochondria with central tubular cristae, and electron-dense iron deposits in the matrix of mitochondria in cardiac muscle; only rare swollen mitochondria are observed (J:75420)
• at 12 weeks, mutant hearts display mitochondrial degeneration; excessive accumulation of abnormal mitochondria displaces fibers to the periphery (J:90401)
• at 7 and 10 weeks, mutants display a marked succinate dehydrogenase deficiency (complex II) in cardiac muscle, with no significant difference in cytochrome c oxidase activity (complex IV) (J:75420)
• at 7 and 10 weeks, mutants show a 77-87% complex II deficiency and a 70-74% aconitase deficiency in cardiac muscle; complex I (NADH dehydrogenase) and III (cytochrome c reductase) activities are also significantly reduced (J:75420)
• Fe-S deficiency in cardiac muscle occurs very early in disease pathology (at 4 weeks), with 50% residual activity, whereas mitochondrial iron accumulation occurs at 4-5 weeks after the onset of heart pathology and Fe-S deficit and serves as a marker of disease end stage (J:90401)
• from 7 weeks onward, reduced Fe-S enzyme activities are associated with lower levels of oxidative stress markers (oxidized proteins) in cardiac muscle, with reduced lipid peroxide levels noted at 9 weeks (J:90401)
• at 10 weeks, mutant mice show increased mitochondrial proliferation in cardiac muscle

homeostasis/metabolism
• at 10 weeks, mutant mice exhibit impaired intramitochondrial iron metabolism, as shown by the presence of small electron-dense iron deposits in mitochondria
• at 7 weeks, mutant mice display normal or slightly increased iron content in cardiac mitochondria relative to wild-type mice (791 108 ng iron/mg protein vs 749 35 ng iron/mg protein, respectively) (J:75420)
• however, at 10 weeks, cardiac mitochondrial iron is significantly increased (1,049 205 ng iron/mg protein vs 579 65 ng iron/mg protein) (J:75420)
• cardiac intramitochondrial iron concentration significantly increases between 8-9 weeks to reach ~2-fold the normal iron content by death (J:90401)

growth/size
• mutant mice begin to lose weight at ~7 weeks of age, reaching a 29% weight reduction at death

behavior/neurological
• mutant mice develop signs of fatigue prior to death

muscle
• at 10 weeks, mutant mice exhibit sparse atrophied myofibrils which are pushed to the periphery, as well as disrupted myofibrils at the positions of intercalated discs (J:75420)
• earlier, at 4 weeks, mutant hearts display abnormal accumulation of lipid droplets and few degenerating fibers; by 5-6 weeks, a gradual reduction in lipid droplets, swollen mitochondria, and disorganized cardiac muscle fibers are observed (J:90401)
• mutant mice display an initial cardiac hypertrophy which develops into a dilated cardiomyopathy without skeletal muscle involvement (J:75420)
• at 7 weeks, hypertrophic cardiomyopathy is rapidly associated with significant geometric remodeling (J:90401)
• antioxidant idebenone delays the cardiac disease onset, progression and death by 1 week, but fails to correct the Fe-S enzyme deficiency and has no effect on the status of lipid peroxidation (oxidative stress) (J:90401)
• at 5 and 7 weeks of age, mutant mice show a 24% and 66% decrease of the shortening fraction, respectively

Mouse Models of Human Disease
OMIM IDRef(s)
Friedreich Ataxia 1; FRDA 229300 J:75420


Mouse Genome Informatics
cn2
    Igf2rtm1Rlj/Igf2r+
Tg(Ckmm-cre)1Lrsn/0

involves: 129 * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
normal phenotype

cellular
• the paternally-inherited Igf2r allele is normally silenced through genomic imprinting so embryos inheriting the floxed Igf2r allele maternally are functionally muscle-specific homozygous knockouts


Mouse Genome Informatics
cn3
    Ikbkbtm2Mka/Ikbkbtm2Mka
Tg(Ckmm-cre)1Lrsn/0

involves: 129/Sv
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
muscle
• under long-term differentiation conditions without medium replenishment, myotubes are 48% less atrophic compared to similarly treated wild-type mouse embryonic fibroblasts
• the number of intermediate fibers is increased compared to in wild-type mice


Mouse Genome Informatics
cn4
    Tfamtm1Lrsn/Tfamtm1Lrsn
Tg(Ckmm-cre)1Lrsn/0

involves: 129S1/Sv * 129X1/SvJ
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Heart histology of Tfamtm1Lrsn/Tfamtm1Lrsn Tg(Ckmm-cre)1Lrsn/0 mice

mortality/aging
• die at 2-4 weeks of age

growth/size
• cessation of weight gain from P10 onwards

cardiovascular system
• dilated
• ECG changes under isofluorane anesthesia
• decrease in peak aortic blood flow velocity under isofluorane anesthesia
• mutants exhibit a significant increase in apoptosis of cardiomyocytes
• however, no evidence of fibrosis, necrosis, or inflammatory cell infiltration is seen in the hearts

homeostasis/metabolism
• levels of aconitase, a mitochondrial enzyme, and nucleus-encoded respiratory chain complex II are not affected
• total glutathione peroxidase enzyme activity is elevated in hearts
• ECG changes under isofluorane anesthesia
• decrease in peak aortic blood flow velocity under isofluorane anesthesia

behavior/neurological
• decreased spontaneous movement from P10 onwards

muscle
• mutants exhibit a significant increase in apoptosis of cardiomyocytes
• however, no evidence of fibrosis, necrosis, or inflammatory cell infiltration is seen in the hearts

cellular
• mutants exhibit a significant increase in apoptosis of cardiomyocytes
• however, no evidence of fibrosis, necrosis, or inflammatory cell infiltration is seen in the hearts
• mosaic respiratory chain deficiency in the myocardium

Mouse Models of Human Disease
OMIM IDRef(s)
Kearns-Sayre Syndrome; KSS 530000 J:51964


Mouse Genome Informatics
cn5
    Erbb2tm1Klee/Erbb2tm1Klee
Tg(Ckmm-cre)1Lrsn/0

Not Specified
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
cardiovascular system
• increase in the numbers of mitochondria and vacuoles in cardiomyoctyes, however cytoskeletal ultrastructure is unchanged
• increase in apoptosis in the ventricles
• decrease in septal thickness
• decrease in posterior ventricular wall thickness
• all mutants develop dilated cardiomyopathy by 6 weeks of age
• exhbiit ventricular enlargement of both the left and right cardiac chambers and a marked increase in heart:body weight ratio
• decrease in fractional shortening, velocity of circumferential fiber shortening and a reduction of the maximum first derivative of left ventricle pressure, indicating depressed myocardium contractility, however no differences in heart rate or left ventricle end-diastolic pressure
• reduction in left ventricle dP/dtmin indicates impaired left ventricle relaxation

muscle
• increase in the numbers of mitochondria and vacuoles in cardiomyoctyes, however cytoskeletal ultrastructure is unchanged
• all mutants develop dilated cardiomyopathy by 6 weeks of age
• exhbiit ventricular enlargement of both the left and right cardiac chambers and a marked increase in heart:body weight ratio
• decrease in fractional shortening, velocity of circumferential fiber shortening and a reduction of the maximum first derivative of left ventricle pressure, indicating depressed myocardium contractility, however no differences in heart rate or left ventricle end-diastolic pressure
• reduction in left ventricle dP/dtmin indicates impaired left ventricle relaxation