Analysis Tools
mortality/aging
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• homozygotes survive for up to 3 weeks of age
• mutants with the slowest growth rates (4 of 8) usually die during the first postnatal week
• mutants with intermediate growth rates die within the second or third week
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growth/size/body
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• at P10, homozygotes are significantly smaller than wild-type littermates
• however, no skeletal abnormalities are observed and failure to thrive is unrelated to nursing difficulties
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• reduction of postnatal growth rate is variable among mice, first evident between P2 and P7, and progressive until death by P18
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behavior/neurological
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• homozygotes display striking and progressive motor deficits
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• homozygotes exhibit progressive limb weakness, as shown by impaired ability to hold onto a bar suspended above the cage for at least 5 sec without falling or scale a 60 degree incline
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• homozygotes display earlier onset of fatigue, as shown by reduced endurance only after 2-3 cycles of immersion into a small room-temperature water bath (vs 10 cycles in wild-type mice)
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hematopoietic system
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• within the bone marrow, all hematopoietic lineages appear to be reduced
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• homozygotes display a hypocellular bone marrow
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nervous system
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• homozygotes display degeneration of large CNS neurons, esp. in the basal ganglia and brainstem
• neurodegeneration is associated with extensive mitochondrial damage, loss of polysomes, clearing of the cytoplasm, a relative absence of rough ER, focal dilation of smooth ER, and ruffling of nuclear membranes
• in P10 basal ganglia, early cellular degeneration includes dispersion of cytoplasm, shedding of ribosomes, and balloning of mitochondria
• in affected brain and brainstem regions, occasional swollen neurites are observed; however, most structures and mitochondria remain intact
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cellular
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• at >P7, homozygotes show extensive mitochondrial injury in affected cardiac muscle cells and degenerating neurons
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adipose tissue
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• homozygotes display a significant reduction in adipose tissue mass
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muscle
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• only 10% of homozygotes display extreme baloon-like cardiac dilatation with thinning of the ventricular wall
• affected myocytes exhibit widespread cellular injury and death associated with mitochondrial injury (swelling and fragmentation) and lipid peroxidation of mitochondrial membranes in severely affected resgions
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• homozygotes display a significant reduction in skeletal muscle mass
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immune system
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• within the bone marrow, all hematopoietic lineages appear to be reduced
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liver/biliary system
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• hepatic glycogen deposits appear coarsely granular and with a tendency towards centrilobular accumulation
• in addition, an abundance of intracellular lipid vacuoles is observed
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cardiovascular system
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• homozygotes with extreme baloon-like cardiac dilatation (10%) display thinning of the ventricular wall
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• only 10% of homozygotes display extreme baloon-like cardiac dilatation with thinning of the ventricular wall
• affected myocytes exhibit widespread cellular injury and death associated with mitochondrial injury (swelling and fragmentation) and lipid peroxidation of mitochondrial membranes in severely affected resgions
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homeostasis/metabolism
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• homozygotes display an abundance of intracellular lipid vacuoles in hepatocytes
• homozygotes with extreme cardiac dilatation exhibit lipid peroxidation of mitochondrial membranes in affected myocytes
• homozygotes without extreme cardiac dilatation show increased accumulation of neutral lipid in myocytes but no mitochondrial injury
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reproductive system
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• ovaries from female homozygotes (4-10 days of age), transplanted to the bursa of wild-type hosts, display all stages of folliculogenesis including corpora lutea and give rise to viable offspring, suggesting normal ovarian function
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integument
