Phenotypes associated with this allele

• Allele Symbol: Fxn^tm2Mkn
• Allele Name: targeted mutation 2, Michel Koenig
• Allele ID: MGI:2177176
• Summary: 2 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
cn1	Fxn^tm2Mkn/Fxn^tm2.1Mkn Tg(Ckmm-cre)1Lrsn/0	involves: 129 * C57BL/6J	MGI:2177207
cn2	Fxn^tm2Mkn/Fxn^tm2.1Mkn Tg(Eno2-cre)39Jme/0	involves: 129 * C57BL/6J	MGI:2177208

Genotype
MGI:2177207

cn1

• 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

Genotype
MGI:2177208

cn2

• Allelic Composition: Fxn^tm2Mkn/Fxn^tm2.1Mkn; Tg(Eno2-cre)39Jme/0
• Genetic Background: involves: 129 * C57BL/6J

mortality/aging

premature death ( J:75420 )

• mutant mice die at 24 9 days after birth

behavior/neurological

abnormal motor coordination/balance ( J:75420 )

• mutant mice display loss of proprioception, as shown by the mis-positioning of the right hind-paw, which the mouse fails to perceive

ataxia ( J:75420 )

• mutant mice exhibit an average onset of ataxia at 12 days after birth

hunched posture ( J:75420 )

abnormal gait ( J:75420 )

• mutant mice develop a rapidly progressive gait abnormality

growth/size/body

cardiac hypertrophy ( J:75420 )

• at 2-3 weeks of age (shortly before or at death), mutants show a significantly increased mean heart to body weight ratio relative to wild-type mice (13.7 6 mg/g vs 5.8 0.5 mg/g, respectively)

decreased body weight ( J:75420 )

• mutant mice exhibit a low birth weight

weight loss ( J:75420 )

• mutants mice show progressive weight loss, with a 18% and 41% weight reduction noted at 7 days after birth and at death, respectively

• by P16, most mutants are moribund and rapidly stop gaining weight; some even rapidly lose weight

decreased body length ( J:75420 )

• at P12, mutants display reduced body length relative to wild-type mice; however, no obvious skeletal abnormalities are observed

postnatal growth retardation ( J:75420 )

• mutant mice display reduced growth rates throughout their lifespan relative to wild-type mice

muscle

muscle phenotype ( J:75420 )

N

abnormal myocardial fiber morphology ( J:75420 )

• at 2 weeks, mutant cardiac muscle contains numerous lipid droplets and giant mitochondria with disorganized cristae

myocardium necrosis ( J:75420 )

dilated cardiomyopathy ( J:75420 )

cardiovascular system

abnormal myocardial fiber morphology ( J:75420 )

• at 2 weeks, mutant cardiac muscle contains numerous lipid droplets and giant mitochondria with disorganized cristae

myocardium necrosis ( J:75420 )

cardiac hypertrophy ( J:75420 )

• at 2-3 weeks of age (shortly before or at death), mutants show a significantly increased mean heart to body weight ratio relative to wild-type mice (13.7 6 mg/g vs 5.8 0.5 mg/g, respectively)

cardiac fibrosis ( J:75420 )

dilated cardiomyopathy ( J:75420 )

cellular

dilated mitochondrion ( J:75420 )

• at 2 weeks, 50% of cardiac mitochondria appear to be swollen in the myofibrils

nervous system

neurodegeneration ( J:75420 )

• mutants exhibit areas of degeneration and necrosis in the dentate nucleus of the cerebellum and the brainstem (esp. in the trigeminal nucleus and tracts, the vestibular system and the cochlear nuclei and nerve)

• in contrast, the spinal cord, dorsal root ganglia and peripheral nerves appear unaffected

spongiform encephalopathy ( J:75420 )

abnormal nerve conduction ( J:75420 )

• upon electromyography, mutants show specific absence of the spinal somatosensory evoked response (H band), indicating a dysfunction in the large myelinated proprioceptive sensory neurons

• in contrast, the small myelinated sensory axons of the tail (heat and pain) have normal velocity

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Friedreich ataxia		DOID:12705		J:75420