Mouse Genome Informatics
hm
    Htttm2Detl/Htttm2Detl
involves: 129P2/OlaHsd * C57BL/6J
Key:
phenotype observed in females WTSI Wellcome Trust Sanger Institute
phenotype observed in males EuPh Europhenome
N normal phenotype
       
behavior/neurological
• the discrepancy between onset age of behavioral and neurological phenotypes is believed to reflect the percentage of C57BL/6 in the strain background (50-75% C57BL/6 - early onset (J:67074), 75-90% C57BL/6 - late onset (J:123681))
• homozygotes are viable and developmentally normal but present symptoms of motor deficits with an onset of ~25 weeks; symptom presentation is variable among individual mutants (J:67074)
• at 20 weeks of age mice performed better in motor learning and motor performance on the accelerated rotarod than wild-type controls (J:123681)
• muscle power as assessed by latency to fall in the hanging wire test is not impaired in 100 week old mice (J:123681)
• during tail suspension, >60% of young homozygotes (15-40 weeks) versus only <20% of wild-type or Hdhtm1Detl homozygotes (carrying a 80 unit CAG repeat) tend to clasp (J:67074)
• homozygotes with a 150 unit CAG repeat exhibit an earlier onset of limb clasping relative to heterozygotes (J:67074)
• clasping behavior produced by tail suspension test is observed in a small number of homozygotes at 20 weeks of age; by 70 - 100 weeks of age clasping behavior is common (J:123681)
• resting tremor observed in animals at 100 weeks of age
• at 5.0 rpm., homozygotes (15-40 weeks) stay for a significantly shorter time on a slowly rotating rod than age-matched heterozygotes
• beginning at 70 weeks of age time to traverse 11 mm round and 5 mm square balance beams is increased as compared to wild-type
• 80% of 100 week old mice fail to traverse the 5 mm beam
• as early as 40 weeks of age, homozygotes exhibit a hindlimb drag while traversing beam
• 90% of 100 week old mice exhibit a hindlimb drag while traversing beam
• significant increase in number of falls on the accelerated rotarod at 100 weeks of age in comparison to wild-type and heterozygotes, however, motor learning is not impaired
• at >40 weeks of age, homozygotes exhibit an early-onset increase in the distance between front and hind paws ('overlap' distance) relative to age-matched heterozygotes
• homozygotes younger than 40 weeks of age tend to exhibit open cage inactivity, suggesting that an increase in mutant allele dose causes an earlier onset of this abnormality (J:67074)
• reduced activity first observed in animals at 70 weeks of age as measured by automated activity cages, by 100 weeks activity is significantly reduced (J:123681)
• young homozygotes (15-40 weeks) exhibit a more severe gait abnormality than age-matched heterozygotes (J:67074)
• 9 out of 10 homozygotes with severe gait disturbance display either clasping or open cage inactivity (J:67074)
• staggering gait/loss of gait pattern is observed in homozygotes at 100 weeks of age (J:123681)
• hindpaw and forepaw stride lengths are reduced in homozygotes at 100 weeks of age as compared to wild-type
• 4 out of 25 mutant mice (250 trials; 25-60 weeks of age) exhibit a convulsive spell consistent with a tonic-clonic seizure; more than one occurrences are noted in two mice during a 10 trial period (J:67074)
• seizures are not observed in mice with higher percentage of C57BL/6 in genetic background (J:123681)

growth/size
• at >25 weeks of age, ~1 in 10 mutants appears significantly smaller than its wild-type littermate; this size difference progresses slowly with age
• progressive weight loss with age
• most significant loss observed between 70 and 100 weeks of age as compared to wild-type

homeostasis/metabolism
N
• homozygotes display normal blood glucose levels relative to wild-type mice (J:67074)

nervous system
N
• homozygotes display no extreme reductions in major brain regions up to 52 weeks of age (J:67074)
• 4 out of 25 mutant mice (250 trials; 25-60 weeks of age) exhibit a convulsive spell consistent with a tonic-clonic seizure; more than one occurrences are noted in two mice during a 10 trial period (J:67074)
• seizures are not observed in mice with higher percentage of C57BL/6 in genetic background (J:123681)
• homozygotes exhibit a 42.8% reduction in striatal neuron number
• mean striatal volume is reduced to 40.4% as compared to wild-type at 100 weeks of age
• striatal dopamine D1 receptor sites are decreased by 79% as compared to wild-type at 100 weeks of age
• striatal dopamine D2 receptor sites are decreased by 42% as compared to wild-type at 100 weeks of age
• striatal dopamine D1 receptor sites are decreased by 86% as compared to wild-type at 100 weeks of age
• striatal dopamine D2 receptor sites are decreased by 32% as compared to wild-type at 100 weeks of age
• mutant mice exhibit significant reactive gliosis in the striatum; notably, neuronal number remains relatively unaffected
• striatal neurons appear atrophic and irregularly shaped
• starting at ~40 weeks, mutants exhibit neuronal intranuclear inclusions (NIIs) predominantly in the striatum; no dystrophic neurites are observed
• starting at ~40 weeks, mutants exhibit neuronal intranuclear inclusions (NIIs) predominantly in the striatum

Mouse Models of Human Disease
OMIM IDRef(s)
Huntington Disease; HD 143100 J:123681