Phenotypes associated with this allele

• Allele Symbol: Htt^tm2Detl
• Allele Name: targeted mutation 2, Peter J Detloff
• Allele ID: MGI:2177757
• Summary: 3 genotypes

Jump to	Allelic Composition	Genetic Background	Genotype ID
hm1	Htt^tm2Detl/Htt^tm2Detl	involves: 129P2/OlaHsd * C57BL/6J	MGI:3043476
ht2	Htt^tm2Detl/Htt^+	B6J.129P2-Htt^tm2Detl	MGI:5698523
ht3	Htt^tm2Detl/Htt^+	involves: 129P2/OlaHsd * C57BL/6J	MGI:3583000

Genotype
MGI:3043476

hm1

• 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

Genotype
MGI:5698523

ht2

• Allelic Composition: Htt^tm2Detl/Htt⁺
• Genetic Background: B6J.129P2-Htt^tm2Detl

nervous system

microgliosis ( J:220868 )

♂ • mice with about 250 CAG repeats exhibit increased proliferation of microglia in the striatum

abnormal striatum morphology ( J:220868 )

♂ • mice with about 250 CAG repeats show a reduction in the striatum volume by 6 months of age but not at 3 months

♂ • striatal metabolites are altered by 9 months of age in mice with about 250 CAG repeats, with lower levels of N-acetylaspartate at 9 months, and lower levels of gamma-aminobutyric acid (GABA), glutamate, NAA, creatine + PCr and increased levels of glutamine and taurine at 12 months of age

decreased neocortex volume ( J:220868 )

♂ • mice with about 250 CAG repeats show a reduction in the neocortex volume by 6 months of age but not at 3 months

brain atrophy ( J:220868 )

♂ • mice backcrossed to C57BL/6J for 8 generations yields mice with about 250 CAG repeats which show acceleration of brain atrophy (striatum and neocortex) compared to mice with 150 or 200 CAG repeats that is most robust between 2 and 6 months of age

decreased oligodendrocyte number ( J:220868 )

♂ • mice with about 250 CAG repeats have decreased numbers of mature oligodendrocytes in the brain at P14

decreased myelin sheath thickness ( J:220868 )

♂ • mice with about 250 CAG repeats exhibit numerous smaller axons that are hypomyelinated with increased G-ratios (diameter of axon/outer diameter of the myelinaged fiber) in the corpus callosum at 12 months of age, indicating thinner myelin sheaths

neuronal intranuclear inclusions ( J:220868 )

♂ • mice with about 250 CAG repeats show nuclear progressive accumulation of mutant HTT aggregates from 6 to 12 months of age

abnormal oligodendrocyte physiology ( J:220868 )

♂ • mice with about 250 CAG repeats exhibit enhanced proliferation of oligodendrocyte precursor cells in the corpus callosum and striatum at 9 and 12 months of age

♂ • however, the number of oligodendrocyte precursor cells is normal

♂ • primary oligodendrocyte precursor cells from P6 mice with about 250 CAG repeats exhibit an extended S-phase

abnormal myelination ( J:220868 )

♂ • mice with about 250 CAG repeats show developmental delay of myelination, with lower levels of all isoforms of myelin basic protein and myelin oligodendrocyte glycoprotein in the striatum at P14

dysmyelination ( J:220868 )

♂ • mice with about 250 CAG repeats show fewer myelinated axons in the corpus callosum at P14

growth/size/body

weight loss ( J:220868 )

♂ • mice with about 250 CAG repeats exhibit lower body weight; they gain body weight normally up to 4 months, stop gaining weight and then lose weight

behavior/neurological

impaired coordination ( J:220868 )

♂ • mice with about 250 CAG repeats exhibit a motor deficit on the balance beam at 6 months of age, spending more time to cross the beam; motor deficits progress with age

hematopoietic system

microgliosis ( J:220868 )

♂ • mice with about 250 CAG repeats exhibit increased proliferation of microglia in the striatum

immune system

microgliosis ( J:220868 )

♂ • mice with about 250 CAG repeats exhibit increased proliferation of microglia in the striatum

homeostasis/metabolism

increased taurine level ( J:220868 )

♂ • mice with about 250 CAG repeats show increased levels of taurine in the striatum at 12 months of age

Mouse Models of Human Disease		DO ID	OMIM ID(s)	Ref(s)
Huntington's disease		DOID:12858	OMIM:143100	J:220868

Genotype
MGI:3583000

ht3

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

mortality/aging

premature death ( J:67074 )

• only 3 of 45 heterozygotes die prior to 1 year of age; heterozygotes typically survive for >1 year

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 )

• heterozygotes are viable and developmentally normal but present symptoms of motor deficits with an onset of ~60 weeks; symptom presentation is variable among individual mutants

limb grasping ( J:67074 )

• during tail suspension, >60% of old heterozygotes (>40 weeks) versus only <20% of wild-type or Hdh^tm1Detl homozygotes (carrying a 80 unit CAG repeat) tend to clasp

• the tendency to clasp is a late-onset trait conferred by the Hdh^tm2Detl allele

abnormal motor coordination/balance ( J:67074 )

• at 5.0 rpm., heterozygotes (15-40 weeks) stay for a significantly shorter time on a slowly rotating rod relative to age-matched wild-type mice

enhanced coordination ( J:123681 )

• at 20 weeks of age mice performed better in motor performance on the accelerated rotarod than wild-type controls

• heterozygotes outperform homozygotes on the rotarod up to 40 weeks of age

impaired balance ( J:123681 )

• beginning at 70 weeks of age time to traverse 11 mm round and 5 mm square balance beam is increased as compared to wild-type

• 50% of 100 week old mice fail to traverse the 5 mm beam

• 63% of 100 week old mice exhibit a hindlimb drag while traversing beam

impaired limb coordination ( J:67074 )

• at >40 weeks of age, heterozygotes show a late-onset increase in the average distance between front and hind paws ('overlap' distance) relative to age-matched wild-type mice or Hdh^tm1Detl heterozygotes (carrying a 80 unit CAG repeat)

abnormal gait ( J:67074 , J:123681 )

• old heterozygotes (greater than 40 weeks) exhibit an abnormal gait relative to wild-type mice (J:67074)

• old (but not young) heterozygotes display a 2-fold increase in stride and base length variation relative to wild-type mice, suggesting that the mutation causes a late-onset variability in gait (J:67074)

• staggering gait observed in animals at 100 weeks of age (J:123681)

short stride length ( J:123681 )

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

decreased locomotor activity ( J:67074 )

• at 15-40 weeks of age, a few heterozygotes remain inactive upon removal of the cage lid whereas all wild-type mice show exploratory activity by walking around the cage

• the proportion of heterozygotes tending to remain inactive increases significantly with age (>40 weeks), indicating that the tendency to be inactive is a late-onset trait conferred by the mutant allele

nervous system

nervous system phenotype ( J:67074 )

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

abnormal dorsal striatum morphology ( J:123681 )

• striatal dopamine D1 receptor sites are decreased by 42% as compared to wild-type at 100 weeks of age

• striatal dopamine D2 receptor sites are decreased by 17% as compared to wild-type at 100 weeks of age

abnormal ventral striatum morphology ( J:123681 )

• striatal dopamine D1 receptor sites are decreased by 50% as compared to wild-type at 100 weeks of ag

• striatal dopamine D2 receptor sites are decreased by 17% 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

neuron degeneration ( J:67074 )

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

growth/size/body

decreased body size ( J:67074 )

• at 52 weeks of age, some heterozygotes are significantly smaller than wild-type littermates

homeostasis/metabolism

homeostasis/metabolism phenotype ( J:67074 )

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