Mouse Genome Informatics
cn1
    Gt(ROSA)26Sortm1Lrsn/Gt(ROSA)26Sor+
Park2tm1Roo/Park2tm1Roo
Slc6a3tm1(cre)Lrsn/Slc6a3+
Tfamtm1Lrsn/Tfamtm1Lrsn

involves: 129S1/Sv * 129S2/SvPas * 129X1/SvJ * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• YFP+ neurons exhibit one or more grossly enlarged, rounded mitochondria in the perinuclear region of the soma and in proximal segment of dendrites with some cells containing fragmented mitochondria and small, spherical mitochondrial clustered around the nucleus
• YFP+ neurons exhibit a progressive reduction in distal axonal mitochondrial numbers compared with control cells
• however, mitochondria in the distal dopamine axons are morphologically spared
• neurons exhibit less intense staining with a retrograde tracer (fluorogold) suggesting impaired retrograde transport and/or uptake of the tracer compared with control cells


Mouse Genome Informatics
cn2
    Slc6a3tm1(cre)Lrsn/Slc6a3+
Sncatm1Nbm/Sncatm1Nbm
Tfamtm1Lrsn/Tfamtm1Lrsn

involves: 129S1/Sv * 129S6/SvEvTac * 129X1/SvJ * C57BL/6 * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
nervous system
• triple mutants show same phenotype as Tfamtm1Lrsn, Slc6a3tm1(cre)Lrsn mice; neuronal inclusions remain indicating that additional lack of Snca is not required for develoment of the Parkonsonian phenotype


Mouse Genome Informatics
cn3
    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/body
• 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
cn4
    Myl1tm1(cre)Sjb/Myl1+
Tfamtm1Lrsn/Tfamtm1Lrsn

involves: 129S1/Sv * 129X1/SvJ * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Skeletal muscle analysis of Tfamtm1Lrsn/Tfamtm1Lrsn Myl1tm1(cre)Sjb/Myl1+ mice

mortality/aging
• death occurs at 4-5 months of age

muscle
• increased muscle fiber size containing enlarged mitochondria with distorted cristae
• shorter contraction times and shorter twitch-relaxation times
• decreased absolute muscle force

cellular
• respiratory chain dysfunction in skeletal muscle

behavior/neurological
• from 3-4 months of age

growth/size/body
• beginning at 4-5 months of age


Mouse Genome Informatics
cn5
    Gt(ROSA)26Sortm1Lrsn/Gt(ROSA)26Sor+
Slc6a3tm1(cre)Lrsn/Slc6a3+
Tfamtm1Lrsn/Tfamtm1Lrsn

involves: 129S1/Sv * 129X1/SvJ * C57BL/6
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Mitochondria abnormalities in Tfamtm1Lrsn/Tfamtm1Lrsn Slc6a3tm1(cre)Lrsn/Slc6a3+ Gt(ROSA)26Sortm1Lrsn/Gt(ROSA)26Sor+ neurons

nervous system
• YFP+ neurons exhibit one or more grossly enlarged, rounded mitochondria in the perinuclear region of the soma and in proximal segment of dendrites with some cells containing fragmented mitochondria and small, spherical mitochondrial clustered around the nucleus
• YFP+ neurons exhibit a progressive reduction in distal axonal mitochondrial numbers compared with control cells

cellular
• smaller mitochondrial and the largest aggregates in a rare number of neurons exhibit reduced import competence compared with mitochondria in control cells

behavior/neurological
• impaired from 20 weeks of age

growth/size/body
• from 20 weeks of age

muscle
• rigidity from 20 weeks of age


Mouse Genome Informatics
cn6
    Tfamtm1Lrsn/Tfamtm1Lrsn
Tg(Ins2-cre)25Mgn/0

involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * DBA
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
homeostasis/metabolism
• decreased blood insulin concentration, onset at 5 week of age
• onset at 27-33 weeks

endocrine/exocrine glands
• normal numbers at 7 weeks, absent at 37 weeks

cellular
• mitochondrial DNA depletion
• respiratory chain dysfunction in pancreatic islets


Mouse Genome Informatics
cn7
    Tfamtm1Lrsn/Tfamtm1Lrsn
Tg(Camk2a-cre)1Lfr/0

involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * DBA
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• at 5-6 months of age, preceded by 1-2 weeks of rapid physical deterioration

nervous system
• in corpus callosum, hippocampus; progressive with age
• degeneration of cortical organization in neocortex
• neuronal apoptosis in neocortex and hippocampus; progressive with age

cellular
• resipratory chain dysfunction in neurons of the neocortex and hippocampus


Mouse Genome Informatics
cn8
    Slc6a3tm1(cre)Lrsn/Slc6a3+
Tfamtm1Lrsn/Tfamtm1Lrsn

involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * SJL
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• mutants have to be terminated at ~45 weeks due to poor general condition

behavior/neurological
• mice aged 14-15 weeks display decreased exploratory activity
• progressive Parkinsonian symptoms are observed, with tremor observed at 20 weeks of age
• apparent limb rigidity is observed at 20 weeks of age

nervous system
• neuron loss results in loss of dopamine in the nigrostriatal system in 20-week old mice
• there are markedly increased ratios of dopamine metabolites to dopamine in the striatum at 20 weeks
• majority of neurons contain small cytoplasmic aggregates, detected at 6 weeks through 43 weeks
• inclusions are present in most dopaminergic midbrain neurons and the mean size increased as the neurodegeneration progressed
• large, partially electron-dense bodies located in dendritic structures close to neuronal somata are observed at 11 weeks; some of these bodies have an amorphous content with a diffuse lining, while others display tubular formations and have distinct double layer membranes which are ultrastructurally typical of mitochondrial membranes
• dopaminergic (DA) neuron loss is observed in the dorsolateral striatum at 12 weeks of age, progressing to involve most of the dorsal and ventral striatum with age
• tyrosine hydroxylase-expressing midbrain neurons show a slow progressive cell loss, which is more marked and starts sooner in the substantia nigra compared to the ventral tegmental area

muscle
• twitching is observed at 20 weeks of age

homeostasis/metabolism
• neuron loss results in loss of dopamine in the nigrostriatal system in 20-week old mice
• there are markedly increased ratios of dopamine metabolites to dopamine in the striatum at 20 weeks

Mouse Models of Human Disease
OMIM IDRef(s)
Parkinson Disease, Mitochondrial 556500 J:119515


Mouse Genome Informatics
cn9
    Tfamtm1Lrsn/Tfamtm1Lrsn
Tg(Myhca-cre)1Lrsn/0

involves: 129S1/Sv * 129X1/SvJ * FVB
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
mortality/aging
• 75% of animals die as neonates
• animals surviving past neonatal stage survive for several months; variable penetrance speculated to be the result of a modifying gene

cardiovascular system

cellular
• respiratory chain dysfunction in heart; variable penetrance speculated to be the result of a modifying gene

Mouse Models of Human Disease
OMIM IDRef(s)
Kearns-Sayre Syndrome; KSS 530000 J:61372