Overview

Also Known As: TS2-neo , G406R

The TS2-neo mutation has the G406R mutation associated with severe Timothy Syndrome (TS2) and an inverted neomycin resistance cassette, all inserted at the end of exon 8 of the CaV1.2 L-type calcium channel locus (Cacna1c). Heterozygous TS2-neo mice exhibit several characteristics of autism spectrum disorder, including repetitive/perseverative stereotypical behavior, decreased social interaction, decreased communication/vocalization, enhanced fear memory and self-injurious scratching. These mice are useful in studying the autism spectrum disorder (ASD) characteristics of Timothy Syndrome.

Donating Investigator

Richard Tsien, Stanford University

Randall L Rasmusson, The State University of New York, University at Buffalo

Glenna C Bett, The State University of New York, University at Buffalo

Genetic overview

Genetic Background	Generation

Cacna1c^tm2Itl

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout, Humanized sequence)	Cacna1c	calcium channel, voltage-dependent, L type, alpha 1C subunit

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Research Applications

Neurobiology Research
Developmental Biology Research
Cell Biology Research

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Base Price

Starting at:

$2,854.50 Domestic price Cryo Recovery

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Details

Detailed Description

The TS2-neo allele has a G406R mutation associated with severe Timothy Syndrome (TS2) and an inverted neomycin resistance cassette, all inserted at the end of exon 8 of the CaV1.2 L-type calcium channel locus (Cacna1c). In similar G406R mutant mice without a neo cassette, expression of the G406R mutation-bearing channel causes death in both heterozygotes and homozygotes. Mice homozygous for the TS2-neo allele are also lethal. However, a single copy of the TS2-neo allele results in 75% lower G406R mutation-bearing channel expression in brain and no expression of the G406R mutation-bearing channel in heart (suggesting transcriptional interference from the neomycin cassette). The attenuated expression diminishes the deleterious effects of mutant L-type channel overactivity and allows heterozygous TS2-neo animals to be viable and fertile. Heterozygous TS2-neo mice exhibit distinct traits strikingly reminiscent of the entire core triad of autism spectrum disorder (ASD): repetitive/perseverative behavior, impaired social behavior, and impaired communication. TS2-neo mice also display enhanced fear memory (reminiscent of persistent memories or abnormal fear associated with ASD), as well as self-injurious scratching.

Development

The TS2-neo mutation was designed by Dr. Randall L. Rasmusson (The State University of New York, University at Buffalo). First, a G->A base pair substitution was introduced (via site-directed mutagenesis) at the end of exon 8 of the CaV1.2 L-type calcium channel locus (Cacna1c) on chromosome 6. This mutation at the intracellular part of the S6 transmembrane segment of domain 1 results in a de novo gain of function missense substitution of glycine to arginine at codon 406 (G406R); a mutation associated with severe Timothy Syndrome (TS2). The targeting vector was designed to introduce this G406R mutation at the end of exon 8, as well as an inverted neomycin resistance cassette 301 bp downstream of the G->A point mutation, thus causing the introduction of a stop codon in exon 8A. The targeting vector was electroporated into (C57BL/6NTac x 129S6/SvEvTac)F1-derived iTL BA1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts. Chimeric mice were bred with unknown animals to establish the mutant colony. TS2-neo mice were then backcrossed with C57BL/6J for at least nine generations prior to sending to The Jackson Laboratory Repository in 2013. Upon arrival, sperm was cryopreserved. To generate the living colony, an aliquot of the frozen sperm was used to fertilize oocytes from C57BL/6J female mice (Stock No. 000664). Heterozygous TS2-neo mice were then bred to wildtype mice from the colony or with C57BL/6J inbred mice to maintain the colony. The donating investigator reports that, at least once during backcrossing, a heterozygous female was bred to a C57BL/6J inbred male (thus the Y chromosome of the congenic strain is of C57BL/6J origin).

Control Suggestions

Wild-type from the colony
000664 C57BL/6J

Additional Information

Considerations for Choosing Controls

Selected References

Bader PL; Faizi M; Kim LH; Owen SF; Tadross MR; Alfa RW; Bett GC; Tsien RW; Rasmusson RL; Shamloo M. 2011. Mouse model of Timothy syndrome recapitulates triad of autistic traits. Proc Natl Acad Sci U S A 108(37):15432-7PubMed: 21878566 MGI: J:176442
Bett GC; Lis A; Wersinger SR; Baizer JS; Diffey ME; Rasmusson RL. 2012. A mouse model of timothy Syndrome: a complex autistic disorder resulting from a point mutation in Cav1.2 North American J Med Sci 5(3):135-140MGI: J:201506

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Genetics

Cacna1c^tm2Itl

Allele Symbol: Cacna1c^tm2Itl

Allele Name	targeted mutation 2, inGenious Targeting Laboratory
Allele Type	Targeted (Null/Knockout, Humanized sequence)
Allele Synonym(s)	targeted mutation 2, inGenious Targeting Laboratory; Cacna1c^tm2Itl
Gene Symbol and Name	Cacna1c, calcium channel, voltage-dependent, L type, alpha 1C subunit
Gene Synonym(s)	D930026N18Rik; CACN2; CACNL1A1; calcium channel, L type, alpha 1 polypeptide, isoform 1 (cardiac muscle); CaV1.2; RATIVS302; TS; LQT8; RIKEN cDNA D930026N18 gene; L-type Cav1.2; (alpha)1 subunit; CACH2; D930026N18Rik; Cchl1a1; CCHL1A1; Cchl1a1; Cav1.2; TS. LQT8
Strain of Origin	(C57BL/6NTac x 129S6/SvEvTac)F1
Chromosome	6
Molecular Note	A G to A transition at the end of exon 8 results in a G406R mutation which appears to be a gain of function mutation that is embryonic lethal in both hetero- and homozygotes. The insertion of an inverted Neo cassette downstream of exon 8, in alternative exon 8A (which is mutually exclusive with exon 8), creates a stop codon in exon 8A (nomenclature used by Splawski et al., 2004) and ameliorates the lethality of the point mutation in heterozygotes.

Disease/Phenotype

Disease Terms

Model with phenotypic similarity to human disease where etiologies involve orthologs. Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

Timothy syndrome

Research Areas By Genotype

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

Neurobiology Research
- Neurodevelopmental Defects
  - Autism
- Neurotransmitter Receptor and Synaptic Vesicle Defects
- Behavioral and Learning Defects
- Channel and Transporter Defects
  - calcium
Developmental Biology Research
- Neurodevelopmental Defects
Cell Biology Research
- Channel and Transporter Defects
  - calcium
- Signal Transduction

Mammalian Phenotype Terms by Genotype

The following phenotype information is associated with a similar, but not exact match to this JAX^® Mice strain

Genotype: Cacna1c^tm2Itl/Cacna1c⁺
involves: 129S6/SvEvTac * C57BL/6J * C57BL/6NTac

behavior/neurological phenotype

abnormal social investigation
- in a social home-cage assay, mice exhibit reduced social preference compared with wild-type mice

decreased exploration in new environment
- Normal - however, mice do not exhibit thigmotaxis
- mice exhibit decreased approach behavior in a novel environment compared with wild-type mice
- mice spent a smaller fraction of time moving, fewer ambulatory movements, and smaller distance traveled in a novel environment compared with wild-type mice

decreased vocalization
- at P6, P8, and P10, mice exhibit shorter duration of ultrasonic vocalization compared with wild-type mice

enhanced contextual conditioning behavior
- mice exhibit increased persistence of contextual fear memory compared with wild-type mice

enhanced cued conditioning behavior
- mice exhibit increased persistence of tone-cued fear memory compared with wild-type mice

increased stereotypic behavior
- mice exhibit repetitive and preservative behaviors in marble burying, Morris water maze (during reversal training), and water Y-maze compared with wild-type mice

mortality/aging

postnatal lethality, complete penetrance

mammalian phenotype

behavior/neurological phenotype
- Normal - mice exhibit normal behavior in a light/dark box test and elevated zero maze
- Normal - mice exhibit normal spatial reference memory acquisition and retrieval in a Morris water maze

Genotype: Cacna1c^tm2Itl/Cacna1c^tm2Itl
involves: 129S6/SvEvTac * C57BL/6J * C57BL/6NTac

mortality/aging

postnatal lethality, complete penetrance

Genotype: Cacna1c^tm2Itl/Cacna1c⁺
involves: 129S6/SvEvTac * C57BL/6NTac

behavior/neurological phenotype

excessive scratching
- mice tend to scratch along one side of body and toward face
- scratching often results in destruction of whiskers

immune system phenotype

dermatitis
- progression is rapid and covers a large area that tends to be on one side as compared to control littermates

integument phenotype

dermatitis
- progression is rapid and covers a large area that tends to be on one side as compared to control littermates

mortality/aging

premature death
- main cause of death is severe dermatitis

nervous system phenotype

abnormal brain morphology
- angles between midline and cerebellum significantly differ from control littermates
- brains are slightly asymmetric as compared to littermates

enlarged lateral ventricles
- circumference of the perimeter does not differ from controls
- total cross sectional area of lateral ventricles is increased as compared to controls

References

Bader PL; Faizi M; Kim LH; Owen SF; Tadross MR; Alfa RW; Bett GC; Tsien RW; Rasmusson RL; Shamloo M. 2011. Mouse model of Timothy syndrome recapitulates triad of autistic traits. Proc Natl Acad Sci U S A 108(37):15432-7PubMed: 21878566 MGI: J:176442
Bett GC; Lis A; Wersinger SR; Baizer JS; Diffey ME; Rasmusson RL. 2012. A mouse model of timothy Syndrome: a complex autistic disorder resulting from a point mutation in Cav1.2 North American J Med Sci 5(3):135-140MGI: J:201506

Additional - Cacna1c^tm2Itl related

Technical Support

Contact Technical Support

Genotyping Protocols
- MELT: Generic LacZ Melt Curve Analysis
- High Resolution Melting: Cacna1c^tm2Itlalternate1
- Probe: Cacna1c^tm2Itl Probe
- Genotyping resources and troubleshooting
Breeding Considerations

Homozygous animals are lethal. When maintaining a live colony, heterozygous mice are bred with wildtype mice from the colony or with C57BL/6J inbred mice (Stock No. 000664).
- Additional Breeding and Husbandry Support
Citation
When using the TS2-neo mouse strain in a publication, please cite the originating article(s) and include JAX stock #019547 in your Materials and Methods section.

Animal Health Reports

Facility Barrier Level Descriptions

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Pricing & Availability

Cryo Recovery

Domestic
International

Live Mouse

Age

Genotype

Price

weeks

Cryorecovery - Pricing

Service	Genotype	Price
	Heterozygous or wildtype for Cacna1c<tm2Itl>

We will fulfill your order by providing at least two carriers for each strain ordered. The total number, sex, and genotypes provided will vary, although typically 8 or more animals are provided. Please check genotypes which will be recovered. While the genotypes of all animals produced will be communicated to you prior to scheduling shipment, the genotypes of animals provided may not reflect the mating scheme and genotypes described in the strain description. Animals are typically ready to ship in 11-14 weeks. If a second recovery is required to produce the minimum number of animals, then delivery time would increase to approximately 25 weeks. If we fail to produce animals of the correct genotype, you will not be charged. We cannot guarantee the reproductive success of mice shipped to your facility. If the mice are lost after the first three days (post-arrival) or do not produce progeny at your facility, a new order and fee will be necessary.

Cryorecovery to establish a Dedicated Supply for greater quantities of mice. Mice recovered can be used to establish a dedicated colony to contractually supply you mice according to your requirements. Price by quotation.

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Frozen Mouse Embryo

$2,595.00 per straw or vial

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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.

Terms Of Use

Terms of Use

General Terms and Conditions

Questions about Terms of Use

Additional Use Restrictions Apply

Notice regarding distribution of this strain.

Licensing Information

Phone: 207-288-6470

Email: TechTran@jax.org

JAX® Mice, Products & Services Conditions of Use

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Also Known As: TS2-neo , G406R

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Additional Information

Selected References

Cacna1ctm2Itl

Allele Symbol: Cacna1ctm2Itl

Disease Terms

Model with phenotypic similarity to human disease where etiologies involve orthologs. Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

Research Areas By Genotype

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

Mammalian Phenotype Terms by Genotype

Genotype: Cacna1ctm2Itl/Cacna1c+involves: 129S6/SvEvTac * C57BL/6J * C57BL/6NTac

behavior/neurological phenotype

mortality/aging

mammalian phenotype

Genotype: Cacna1ctm2Itl/Cacna1ctm2Itlinvolves: 129S6/SvEvTac * C57BL/6J * C57BL/6NTac

mortality/aging

Genotype: Cacna1ctm2Itl/Cacna1c+involves: 129S6/SvEvTac * C57BL/6NTac

behavior/neurological phenotype

immune system phenotype

integument phenotype

mortality/aging

nervous system phenotype

References

Additional - Cacna1ctm2Itl related

Genotyping Protocols

Breeding Considerations

Citation

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200

Live Mouse

Cryorecovery - Pricing

Related Products and Services

Payment Terms and Conditions

The Jackson Laboratory's Genotype Promise

Terms of Use

Additional Use Restrictions Apply

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Cacna1c^tm2Itl

Allele Symbol: Cacna1c^tm2Itl

Genotype: Cacna1c^tm2Itl/Cacna1c⁺
involves: 129S6/SvEvTac * C57BL/6J * C57BL/6NTac

Genotype: Cacna1c^tm2Itl/Cacna1c^tm2Itl
involves: 129S6/SvEvTac * C57BL/6J * C57BL/6NTac

Genotype: Cacna1c^tm2Itl/Cacna1c⁺
involves: 129S6/SvEvTac * C57BL/6NTac

Additional - Cacna1c^tm2Itl related