Mouse Genome Informatics
involves: 129S7/SvEvBrd * C57BL/6J
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype

Histological findings indicating neurodegeneration in Ttpatm1Hsz/Ttpatm1Hsz mice

• at 18 months, mutant showed tremors
• at one year of age, mutants on an alpha-tocopherol-normal and -deficient diet displayed a mild ataxia which worsened with increasing age
• at 18 months, mutants displayed a significantly shorter step length, and poor performance on the accelerating rotating rod apparatus relative to wild-type
• performance on rotarod improved with alpha-tocopherol supplementation
• at 18 months, some mutants displayed a dystonic posture of the hindlimbs when lifted by the tail
• at one year of age, mutants on an alpha-tocopherol-normal and -deficient diet displayed head shaking; this phenotype became worse with increasing age
• at 18 months, mutants exhibited paresis in the hindlimbs while walking

• at 10.5 dpc, live embryos in the uteri of pregnant homozygous null mice appeared abnormal, and the number of trophoblast cells was significantly reduced
• embryonic blood vessels were undetectable in the mutant trophoblast
• the placental failure was effectively reversed by alpha-tocopherol or synthetic antioxidant dietary supplement
• at 10.5 dpc, the labyrinth region of placentas from pregnant homozygous null females was abnormally small

• mutant brain tissues displayed increased lipid peroxidation relative to wild-type
• in particular, massive lipofuscin accumulation was observed in the dorsal root ganglion cells, the outer segment of photoreceptor cells, and the spinal anterior horn cells (i.e. in degenerating neurons)
• all these abnormalities were suppressed with alpha-tocopherol supplementation
• when fed a normal diet (36 mg of alpha-tocopherol/kg diet), homozygous null mice displayed a 100% reduction in plasma vitamin E (alpha-tocopherol) concentration relative to wild-type

• at 18 months, some mutants displayed a dystonic posture of the hindlimbs when lifted by the tail
• at 20 months, skeletal muscles displayed the presence of angulated atrophic fibers
• at 20 months, skeletal muscles displayed variability in fiber size

reproductive system
• homozygous null females became pregnant after mating but failed to deliver offspring (J:67046)
• over 70% of embryos died in the uteri of homozygous null mice at 11.5 dpc (J:67046)
• the proportion of live embryos decreased significantly between 11.5 and 14.5 dpc (J:67046)

• at 20 months, the mutant retina contained disorganized photoreceptors displaying decreased thickness of the outer layer and the rod inner and outer segments
• these defects were exacerbated in mutant mice on an alpha-tocopherol-deficient diet, much more subtle in wild-type mice on a -deficient diet, and almost reversible upon alpha-tocopherol supplementation
• retinal degeneration became evident at 20 months of age; no histological evidence of degeneration was noted at 12 months
• ERGs revealed that both the a-wave (from Muller cells and inner neuronal layers) and b-waves (from photoreceptor cells) were significantly decreased in mutant mice maintained on a normal diet

nervous system
• in the spinal cord, anterior horn cells showed a mild degeneration with fibrillary gliosis
• on an alpha-tocopherol-deficient diet, the lumbar potential of somatosensory-evoked potentials (SEPs), originating from the spinal nerve roots, remained unaffected in mutant mice; in contrast, the cortical potential of SEPs almost disappeared in mutant mice relative to wild-type
• at 20 months, the mutant brain exhibited degeneration of the posterior column and posterior column nucleus with fiber loss, astrocytic proliferation, and abundance of axonal spheroids

Mouse Models of Human Disease
Vitamin E, Familial Isolated Deficiency Of; VED 277460 J:67046