Phenotypes Associated with This Genotype

Genotype
MGI:2177207

• Allelic Composition: Fxn^tm2Mkn/Fxn^tm2.1Mkn; Tg(Ckmm-cre)1Lrsn/0
• Genetic Background: involves: 129 * C57BL/6J

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

mortality/aging

premature death ( J:75420 , J:90401 )

• mutant mice die at 76 10 days (10-12 weeks) (J:75420)

• antioxidant idebenone delays death by 1 week (J:90401)

cardiovascular system

abnormal myocardial fiber morphology ( J:75420 , 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)

abnormal myocardial fiber mitochondrial morphology ( J:75420 )

• 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

myocardium necrosis ( J:75420 )

• by 10 weeks, mutant mice show myocardial degeneration with cytoplasmic vacuolization in myocytes, indicating necrosis

increased heart iron level ( J:75420 , J:90401 )

• 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)

thick interventricular septum ( J:90401 )

• starting at 5 weeks, mutant hearts show a significantly increased ventricular septum wall thickness

cardiac hypertrophy ( J:75420 )

• 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

heart left ventricle hypertrophy ( J:75420 )

increased heart left ventricle weight ( J:90401 )

• starting at 5 weeks, mutant hearts exhibit a significantly increased left ventricular mass

increased heart left ventricle wall thickness ( J:75420 )

• by 10 weeks, mutant mice display notable thickening of the left ventricular wall

increased heart left ventricle posterior wall thickness ( J:90401 )

• starting at 5 weeks, mutant hearts show significantly increased left ventricular posterior wall thickness

dilated heart left ventricle ( J:90401 )

• starting at 5 weeks, mutant hearts display a significant increase in left ventricle diastolic and systolic diameters

cardiac fibrosis ( J:75420 )

• by 10 weeks, mutant mice show post-necrotic fibrosis in cardiac muscle

dilated cardiomyopathy ( J:75420 , 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)

decreased cardiac output ( J:90401 )

• at 8 weeks of age, mutant mice show a 67% reduction of resting cardiac output, associated with saturated hypertrophy

decreased heart ventricle muscle contractility ( J:90401 )

• at 5 and 7 weeks of age, mutant mice show a 24% and 66% decrease of the shortening fraction, respectively

prolonged PR interval ( J:90401 )

• 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

abnormal mitochondrial morphology ( J:90401 )

• at 12 weeks, mutant hearts display mitochondrial degeneration; excessive accumulation of abnormal mitochondria displaces fibers to the periphery

abnormal myocardial fiber mitochondrial morphology ( J:75420 )

• 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

abnormal respiratory electron transport chain ( J:75420 , 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)

increased mitochondrial fission ( J:75420 )

• at 10 weeks, mutant mice show increased mitochondrial proliferation in cardiac muscle

homeostasis/metabolism

abnormal iron homeostasis ( J:75420 )

• at 10 weeks, mutant mice exhibit impaired intramitochondrial iron metabolism, as shown by the presence of small electron-dense iron deposits in mitochondria

increased heart iron level ( J:75420 , J:90401 )

• 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/body

cardiac hypertrophy ( J:75420 )

• 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

heart left ventricle hypertrophy ( J:75420 )

weight loss ( J:75420 )

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

behavior/neurological

fatigue ( J:75420 )

• mutant mice develop signs of fatigue prior to death

muscle

abnormal myocardial fiber morphology ( J:75420 , 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)

abnormal myocardial fiber mitochondrial morphology ( J:75420 )

• 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

myocardium necrosis ( J:75420 )

• by 10 weeks, mutant mice show myocardial degeneration with cytoplasmic vacuolization in myocytes, indicating necrosis

heart left ventricle hypertrophy ( J:75420 )

dilated cardiomyopathy ( J:75420 , 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)

decreased heart ventricle muscle contractility ( 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		DO ID	OMIM ID(s)	Ref(s)
Friedreich ataxia		DOID:12705		J:75420