Phenotypes Associated with This Genotype

Genotype
MGI:3043476

• Allelic Composition: Htt^tm2Detl/Htt^tm2Detl
• Genetic Background: involves: 129P2/OlaHsd * C57BL/6J

• ♀: phenotype observed in females
• ♂: phenotype observed in males
• N: normal phenotype

behavior/neurological

abnormal behavior ( J:123681 )

• 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))

abnormal motor capabilities/coordination/movement ( J:67074 , 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)

limb grasping ( J:67074 , J:123681 )

• during tail suspension, >60% of young homozygotes (15-40 weeks) versus only <20% of wild-type or Hdh^tm1Detl 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)

tremors ( J:123681 )

• resting tremor observed in animals at 100 weeks of age

abnormal motor coordination/balance ( J:67074 )

• at 5.0 rpm., homozygotes (15-40 weeks) stay for a significantly shorter time on a slowly rotating rod than age-matched heterozygotes

impaired balance ( J:123681 )

• 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

impaired coordination ( J:123681 )

• 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

impaired limb coordination ( J:67074 )

• 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

abnormal gait ( J:67074 , 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)

short stride length ( J:123681 )

• hindpaw and forepaw stride lengths are reduced in homozygotes at 100 weeks of age as compared to wild-type

decreased locomotor activity ( J:67074 , J:123681 )

• 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)

tonic-clonic seizures ( J:67074 , J:123681 )

• 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/body

decreased body size ( J:67074 )

• at >25 weeks of age, ~1 in 10 mutants appears significantly smaller than its wild-type littermate; this size difference progresses slowly with age

weight loss ( J:123681 )

• progressive weight loss with age

• most significant loss observed between 70 and 100 weeks of age as compared to wild-type

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:67074 )

N • homozygotes display normal blood glucose levels relative to wild-type mice

nervous system

nervous system phenotype ( J:67074 )

N • homozygotes display no extreme reductions in major brain regions up to 52 weeks of age

tonic-clonic seizures ( J:67074 , J:123681 )

• 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)

abnormal striatum morphology ( 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

abnormal dorsal striatum morphology ( J:123681 )

• 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

abnormal ventral striatum morphology ( J:123681 )

• 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

gliosis ( J:67074 )

• mutant mice exhibit significant reactive gliosis in the striatum; notably, neuronal number remains relatively unaffected

abnormal neuron morphology ( J:123681 )

• striatal neurons appear atrophic and irregularly shaped

neuron degeneration ( J:67074 )

• starting at ~40 weeks, mutants exhibit neuronal intranuclear inclusions (NIIs) predominantly in the striatum; no dystrophic neurites are observed

neuronal intranuclear inclusions ( J:67074 )

• starting at ~40 weeks, mutants exhibit neuronal intranuclear inclusions (NIIs) predominantly in the striatum

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Huntington's disease		DOID:12858	OMIM:143100	J:123681