Description

Strain Information

Former Names B6.129P2-Hdtm2Detl/J    (Changed: 13-DEC-07 ) B6.129P2-Hdhtm2Detl/J    (Changed: 19-SEP-07 ) STOCK Hdhtm2Detl/J    (Changed: 15-DEC-04 ) Type Mutant Stock; Targeted Mutation; Additional information on Genetically Engineered Mutant Mice. Mating System +/+ sibling x Heterozygote         (Female x Male) Species laboratory mouse Generation N9+ (14-OCT-08)   Donating Investigator Gillian Bates,   United Medical and Dental Schools

Description
Mice homozygous for the targeted allele are viable and fertile. At 15-40 weeks of age mice carrying this allele on a segregating C57BL/6 and 129P2 background exhibit an abnormal gait, clasping behavior and diminished exploratory activity. Infrequent tonic-clonic like seizures may also be observed. Mice with a higher percentage of C57BL/6 in their genetic background develop behavioral and neurological phenotypes at a much later age (70-100 weeks). (Heng MY et al. 2007) Mutant mice may be noticeably smaller than wild-type littermates. Increased glial fibrillary acidic protein immunoreactivity is present in the striatum and ubiquititin- and huntingtin-positive neuronal intranuclear inclusions (NIIs) are detected throughout the dorsal striatum, nucleus accumbens and to a lesser extent other regions of the brain. Onset of symptoms occurs earlier for homozygotes than for heterozygotes.This mutant mouse strain represents a model that may be useful in studies related to Huntington's disease.

Development
In the first step of a two step procedure, exon 1 was replaced with the selectable marker Hprt in 129P2/OlaHsd-derived HM1 embryonic stem (ES) cells. A second round of targeting was performed to replace Hprt with exon 1 sequence including a 150 CAG repeat segment. Correctly targeted ES cells were injected into C57BL/6J blastocysts.

Control Information

	Control
	Wild-type from the colony
	000664 C57BL/6J
Considerations for Choosing Controls

Related Strains

Strains carrying other alleles of Htt

003454	B6.129-Htttm3Mem/J
003597	B6.129-Htttm4Mem/J
003598	B6.129-Htttm5Mem/J
002688	B6.129S4-Htttm1Mem/J
003453	STOCK Htttm2Mem/J
003455	STOCK Htttm4Mem/J
003456	STOCK Htttm5Mem/J

View Strains carrying other alleles of Htt     (7 strains)

Additional Web Information

Congenic Nomenclature

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms

Huntington Disease; HD - Models with phenotypic similarity to human disease where etiologies involve orthologs.1

1 Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

The following phenotype information may relate to a genetic background differing from this JAX^® Mice strain.

Htt^tm2Detl/Htt⁺

        involves: 129P2/OlaHsd * C57BL/6J

• behavior/neurological phenotype
• abnormal behavior (MGI Ref ID 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 (MGI Ref ID 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
• abnormal gait (MGI Ref ID J:67074)
  • old heterozygotes (>40 weeks) exhibit an abnormal gait relative to wild-type mice
  • 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
  • staggering gait observed in animals at 100 weeks of age
• abnormal motor coordination/ balance (MGI Ref ID 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 (MGI Ref ID 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 (MGI Ref ID 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 (MGI Ref ID 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)
• hypoactivity (MGI Ref ID 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
• limb grasping (MGI Ref ID 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
• short stride length (MGI Ref ID J:123681)
  • hindpaw and forepaw stride lengths are reduced in heterozygotes at 100 weeks of age as compared to wild-type
• nervous system phenotype
• *normal* nervous system phenotype (MGI Ref ID J:67074)
  • heterozygotes display no extreme reductions in major brain regions up to 52 weeks of age
• abnormal dorsal striatum morphology (MGI Ref ID 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 (MGI Ref ID 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 (MGI Ref ID J:67074)
  • mutant mice exhibit significant reactive gliosis in the striatum; notably, neuronal number remains relatively unaffected
• neuron degeneration (MGI Ref ID J:67074)
  • starting at ~40 weeks, mutants exhibit neuronal intranuclear inclusions (NIIs) predominantly in the striatum; however, no dystrophic neurites are observed
• growth/size phenotype
• decreased body size (MGI Ref ID J:67074)
  • at 52 weeks of age, some heterozygotes are significantly smaller than wild-type littermates
• life span-post-weaning/aging
• premature death (MGI Ref ID J:67074)
  • only 3 of 45 heterozygotes die prior to 1 year of age; heterozygotes typically survive for >1 year
• homeostasis/metabolism phenotype
• *normal* homeostasis/metabolism phenotype (MGI Ref ID J:67074)
  • heterozygotes display normal blood glucose levels relative to wild-type mice

Htt^tm2Detl/Htt^tm2Detl

        involves: 129P2/OlaHsd * C57BL/6J

• behavior/neurological phenotype
• abnormal behavior (MGI Ref ID 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 (MGI Ref ID J:67074)
  • 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
  • at 20 weeks of age mice performed better in motor learning and motor performance on the accelerated rotarod than wild-type controls
  • muscle power as assessed by latency to fall in the hanging wire test is not impaired in 100 week old mice
• abnormal gait (MGI Ref ID J:67074)
  • young homozygotes (15-40 weeks) exhibit a more severe gait abnormality than age-matched heterozygotes
  • 9 out of 10 homozygotes with severe gait disturbance display either clasping or open cage inactivity
  • staggering gait/loss of gait pattern is observed in homozygotes at 100 weeks of age
• abnormal motor coordination/ balance (MGI Ref ID 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 (MGI Ref ID 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 (MGI Ref ID 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 (MGI Ref ID 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
• hypoactivity (MGI Ref ID J:67074)
  • 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
  • reduced activity first observed in animals at 70 weeks of age as measured by automated activity cages, by 100 weeks activity is significantly reduced
• limb grasping (MGI Ref ID J:67074)
  • 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
  • homozygotes with a 150 unit CAG repeat exhibit an earlier onset of limb clasping relative to heterozygotes
  • 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
• short stride length (MGI Ref ID J:123681)
  • hindpaw and forepaw stride lengths are reduced in homozygotes at 100 weeks of age as compared to wild-type
• tremors (MGI Ref ID J:123681)
  • resting tremor observed in animals at 100 weeks of age
• tonic-clonic seizures (MGI Ref ID 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
  • seizures are not observed in mice with higher percentage of C57BL/6 in genetic background
• growth/size phenotype
• decreased body size (MGI Ref ID 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 (MGI Ref ID 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 phenotype
• *normal* homeostasis/metabolism phenotype (MGI Ref ID J:67074)
  • homozygotes display normal blood glucose levels relative to wild-type mice
• nervous system phenotype
• *normal* nervous system phenotype (MGI Ref ID J:67074)
  • homozygotes display no extreme reductions in major brain regions up to 52 weeks of age
• abnormal neuron morphology (MGI Ref ID J:123681)
  • striatal neurons appear atrophic and irregularly shaped
• neuron degeneration (MGI Ref ID J:67074)
  • starting at ~40 weeks, mutants exhibit neuronal intranuclear inclusions (NIIs) predominantly in the striatum; no dystrophic neurites are observed
• neuronal intranuclear inclusions (MGI Ref ID J:67074)
  • starting at ~40 weeks, mutants exhibit neuronal intranuclear inclusions (NIIs) predominantly in the striatum
• abnormal striatum morphology (MGI Ref ID 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 (MGI Ref ID 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 (MGI Ref ID 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 (MGI Ref ID J:67074)
  • mutant mice exhibit significant reactive gliosis in the striatum; notably, neuronal number remains relatively unaffected
• tonic-clonic seizures (MGI Ref ID 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
  • seizures are not observed in mice with higher percentage of C57BL/6 in genetic background

View Research Applications

Research Applications

This mouse can be used to support research in many areas including:

Htt^tm2Detl related

Mouse/Human Gene Homologs
Huntington's disease (chorea)

Neurobiology Research
Cortical Defects
Huntington's disease
Neurodegeneration

Genes & Alleles

Gene & Allele Information

Allele Symbol		Htttm2Detl
Allele Name		targeted mutation 2, Peter J Detloff
Allele Type		Targeted (knock-in)
Common Name(s)		CHL2; Hdh(CAG)150; HdhQ150; HdhCAG150;
Strain of Origin		129P2/OlaHsd-Hprt1
ES Cell Line Name		HM-1
ES Cell Line Strain		129P2/OlaHsd-Hprt1
Gene Symbol and Name		Htt, huntingtin
Chromosome		5
Gene Common Name(s)		AI256365; C430023I11Rik; HD; Hd; Hdh; Huntington disease (human); Huntington disease gene homolog; IT15; RIKEN cDNA C430023I11 gene; expressed sequence AI256365;
Molecular Note		This allele carries 150 CAG repeat units in the first exon of the endogenous gene. [MGI Ref ID J:67074]

Genotyping

Genotyping Information

Genotyping Protocols

Htt^tm2Detl, STD PCR, vers. 1

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

Heng MY; Tallaksen-Greene SJ; Detloff PJ; Albin RL. 2007. Longitudinal evaluation of the Hdh(CAG)150 knock-in murine model of Huntington's disease. J Neurosci 27(34):8989-98. [PubMed: 17715336]  [MGI Ref ID J:123681]

Lin CH; Tallaksen-Greene S; Chien WM; Cearley JA; Jackson WS; Crouse AB; Ren S; Li XJ; Albin RL; Detloff PJ. 2001. Neurological abnormalities in a knock-in mouse model of Huntington's disease. Hum Mol Genet 10(2):137-44. [PubMed: 11152661]  [MGI Ref ID J:67074]

Additional References

Htt^tm2Detl related

Bjorkqvist M; Wild EJ; Thiele J; Silvestroni A; Andre R; Lahiri N; Raibon E; Lee RV; Benn CL; Soulet D; Magnusson A; Woodman B; Landles C; Pouladi MA; Hayden MR; Khalili-Shirazi A; Lowdell MW; Brundin P; Bates GP; Leavitt BR; Moller T; Tabrizi SJ. 2008. A novel pathogenic pathway of immune activation detectable before clinical onset in Huntington's disease. J Exp Med 205(8):1869-77. [PubMed: 18625748]  [MGI Ref ID J:138558]

Brooks SP; Betteridge H; Trueman RC; Jones L; Dunnett SB. 2006. Selective extra-dimensional set shifting deficit in a knock-in mouse model of Huntington's disease. Brain Res Bull 69(4):452-7. [PubMed: 16624677]  [MGI Ref ID J:112811]

Chiang MC; Chen HM; Lee YH; Chang HH; Wu YC; Soong BW; Chen CM; Wu YR; Liu CS; Niu DM; Wu JY; Chen YT; Chern Y. 2007. Dysregulation of C/EBPalpha by mutant Huntingtin causes the urea cycle deficiency in Huntington's disease. Hum Mol Genet 16(5):483-98. [PubMed: 17213233]  [MGI Ref ID J:121854]

Dixon KT; Cearley JA; Hunter JM; Detloff PJ. 2004. Mouse Huntington's disease homolog mRNA levels: variation and allele effects. Gene Expr 11(5-6):221-31. [PubMed: 15200234]  [MGI Ref ID J:90356]

Gonitel R; Moffitt H; Sathasivam K; Woodman B; Detloff PJ; Faull RL; Bates GP. 2008. DNA instability in postmitotic neurons. Proc Natl Acad Sci U S A 105(9):3467-72. [PubMed: 18299573]  [MGI Ref ID J:132766]

Kennedy L; Evans E; Chen CM; Craven L; Detloff PJ; Ennis M; Shelbourne PF. 2003. Dramatic tissue-specific mutation length increases are an early molecular event in Huntington disease pathogenesis. Hum Mol Genet 12(24):3359-67. [PubMed: 14570710]  [MGI Ref ID J:136414]

Kim YJ; Sapp E; Cuiffo BG; Sobin L; Yoder J; Kegel KB; Qin ZH; Detloff P; Aronin N; DiFiglia M. 2006. Lysosomal proteases are involved in generation of N-terminal huntingtin fragments. Neurobiol Dis 22(2):346-56. [PubMed: 16423528]  [MGI Ref ID J:111314]

Orr AL; Li S; Wang CE; Li H; Wang J; Rong J; Xu X; Mastroberardino PG; Greenamyre JT; Li XJ. 2008. N-terminal mutant huntingtin associates with mitochondria and impairs mitochondrial trafficking. J Neurosci 28(11):2783-92. [PubMed: 18337408]  [MGI Ref ID J:133021]

Tallaksen-Greene SJ; Crouse AB; Hunter JM; Detloff PJ; Albin RL. 2005. Neuronal intranuclear inclusions and neuropil aggregates in Hdh(CAG(150)) knockin mice. Neuroscience 131(4):843-52. [PubMed: 15749339]  [MGI Ref ID J:96770]

Trushina E; Du Charme J; Parisi J; McMurray CT. 2006. Neurological abnormalities in caveolin-1 knock out mice. Behav Brain Res 172(1):24-32. [PubMed: 16750274]  [MGI Ref ID J:110712]

Wang CE; Tydlacka S; Orr AL; Yang SH; Graham RK; Hayden MR; Li S; Chan AW; Li XJ. 2008. Accumulation of N-terminal mutant huntingtin in mouse and monkey models implicated as a pathogenic mechanism in Huntington's disease. Hum Mol Genet 17(17):2738-51. [PubMed: 18558632]  [MGI Ref ID J:138148]

Woodman B; Butler R; Landles C; Lupton MK; Tse J; Hockly E; Moffitt H; Sathasivam K; Bates GP. 2007. The Hdh(Q150/Q150) knock-in mouse model of HD and the R6/2 exon 1 model develop comparable and widespread molecular phenotypes. Brain Res Bull 72(2-3):83-97. [PubMed: 17352931]  [MGI Ref ID J:128653]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           AX11

Colony Maintenance

Breeding & Husbandry	This strain originated on a B6;129P2 background. It has been backcrossed to C57BL/6J for at least eight generations(12/20/02)in the laboratory of Dr. Gillian Bates before being donated to the IMR. Expected coat color is black.
Mating System	+/+ sibling x Heterozygote         (Female x Male)
Diet Information	LabDiet® 5K52/5K67

Purchasing information

Pricing, Supply Level & Notes, Controls, General Terms & Conditions

Pricing

Supply Details

Standard Supply

Repository-Live. A collection of over 1000 strains maintained as live colonies. Individual colonies are sized to meet current customer demand. Delivery for orders of 10 mice or less ranges on average from one to eight weeks; mice are generally shipped between four to six weeks of age with a maximum shipping age of ~nine weeks. Colony sizes do not generally support stringent age specifications for large volumes of mice; however custom orders and larger quantities of mice are easily arranged. Estimated ship dates for all orders provided within 48 hours of order placement.

Supply Notes

Usually shipped between four and eight weeks of age. This strain is included in the Induced Mutant Resource Colony collection. Genomic DNA is available for this strain from the Mouse DNA Resource.

Control Information

	Control
	Wild-type from the colony
	000664 C57BL/6J
Considerations for Choosing Controls
USA, Canada and Mexico - Control Pricing Information for Genetically Engineered Mutant Strains.
International - Control Pricing Information for Genetically Engineered Mutant Strains.

General Terms and Conditions

See Terms of Use

The Jackson Laboratory's Genotype Promise

The Jackson Laboratory has rigorous genetic quality control and mutant gene genotyping programs to ensure the genetic background of JAX^® Mice strains as well as the genotypes of strains with identified molecular mutations. JAX^® Mice strains are only made available to researchers after meeting our standards. However, the phenotype of each strain may not be fully characterized and/or captured in the strain data sheets. Therefore, we cannot guarantee a strain's phenotype will meet all expectations. To ensure that JAX^® Mice will meet the needs of individual research projects or when requesting a strain that is new to your research, we suggest ordering and performing tests on a small number of mice to determine suitability for your particular project.

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Ordering and Purchasing Information

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Contact Information
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Tel: 800.422.6423 or 207.288.5845
Fax: 207.288.6150
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Terms of Use

Terms of Use

General Terms and Conditions

For Licensing and Use Restrictions view the link(s) below:
- Use of MICE by companies or for-profit entities requires a license prior to shipping.

Contact information

General inquiries

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phone:	207-288-6470
fax:	207-288-6655

JAX^® Mice & Services Conditions of Use

“Each recipient institution, including its employees and other researchers under its control (RECIPIENT), of mice or services using mice from The Jackson Laboratory (TJL) agrees that such mice, descendants of those mice derived by inbreeding or crossbreeding, including unmodified derivatives of those mice or their descendants (“MICE”) shall not be: (i) used for any purpose other than the internal research of the RECIPIENT, (ii) sold or otherwise provided to any third party for any use, or (iii) provided to any agent or other third party to provide breeding or other services with respect to MICE. Acceptance of MICE from TJL shall be deemed agreement by RECIPIENT to these conditions, and departure from these conditions requires The Jackson Laboratory’s prior written authorization.”

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