Overview

This strain may be useful for generating conditional mutants for applications related to the neurodevelopmental and neurodegenerative disorder called hereditary motor and sensory neuropathy associated with agenesis of the corpus callosum (HMSN/ACC). These mice possess loxP sites flanking exon 18 of the Slc12a6 gene, a K⁺/Cl^- cotransporter associated with HMSN/ACC.

Donating Investigator

Guy Rouleau, Universite de Montreal

Genetic overview

Genetic Background	Generation

Slc12a6^tm1Garo

Allele Type	Gene Symbol	Gene Name
Targeted (Conditional ready (e.g. floxed), No functional change)	Slc12a6	solute carrier family 12, member 6

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Research Applications

Research Tools
Neurobiology Research

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Base Price

Starting at:

$2,854.50 Domestic price Cryo Recovery

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Details

Detailed Description

Slc12a6 is a member of the solute carrier family that encodes the K⁺/Cl^- cotransporter 3 (KCC3 or SLC12A6). KCC3 has a role in ion homeostasis and is associated with the neurodevelopmental and neurodegenerative disorder called hereditary motor and sensory neuropathy associated with agenesis of the corpus callosum (HMSN/ACC). Most HMSN/ACC patients carry a deletion in exon 18 (a conserved splice donor site) that results in a stop codon at position 813 (Thr813X). KCC3 is expressed in brain, kidney, muscle lung and heart.

These mutant mice possess loxP sites flanking exon 18 of the Slc12a6 gene. Mice that are homozygous for this allele are viable and fertile. When bred to mice that express Cre recombinase, the resulting offspring will have exon 18 deleted in the cre-expressing tissues resulting in a C terminal truncation of the protein mimicking the human HMSN/ACC mutation. These mice may be useful in generating conditional knockouts for studying the role of KCC3 in the central and peripheral nervous systems.

For example, when bred to mice carrying Tg(Syn1-cre)671 Jxm (see Stock No. 003966), Cre recombinase expression in neuronal cells results in hyperactivity, reduced pain sensitivity, axonal degeneration, axon swelling, and hypoplasia of the corpus callosum.

Development

A targeting vector was designed to insert a a frt-flanked neomycin resistance (neo) cassette and a loxP site upstream of exon 18 and a second loxP site downstream of exon 18. The construct was electroporated into (129X1/SvJ x 129S1/Sv)F1-derived R1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6 blastocysts and the resulting chimeric mice were crossed to C57BL/6 mice to establish the colony. Mutant mice backcrossed with C57BL/6 inbred mice for at least six generations were sent to The Jackson Laboratory Repository in 2012 (see SNP results below). Upon arrival, males were used to cryopreserve sperm. To establish the living mouse colony, an aliquot of the frozen sperm was used to fertilize C57BL/6J oocytes (Stock No. 000664).

A 32 SNP (single nucleotide polymorphism) panel analysis, with 27 markers covering all 19 chromosomes and the X chromosome, as well as 5 markers that distinguish between the C57BL/6J and C57BL/6N substrains, was performed on the first generation rederived living colony at The Jackson Laboratory Repository. While the 27 markers throughout the genome suggested a C57BL/6 genetic background, all 5 markers that determine C57BL/6J from C57BL/6N were found to be segregating. These data suggest the mice sent to The Jackson Laboratory Repository were on a C57BL/6N genetic background.

Control Suggestions

Wild-type from the colony

Approximate Controls

Additional Information

Considerations for Choosing Controls

Selected References

Shekarabi M; Moldrich RX; Rasheed S; Salin-Cantegrel A; Laganiere J; Rochefort D; Hince P; Huot K; Gaudet R; Kurniawan N; Sotocinal SG; Ritchie J; Dion PA; Mogil JS; Richards LJ; Rouleau GA. 2012. Loss of neuronal potassium/chloride cotransporter 3 (KCC3) is responsible for the degenerative phenotype in a conditional mouse model of hereditary motor and sensory neuropathy associated with agenesis of the corpus callosum. J Neurosci 32(11):3865-76PubMed: 22423107 MGI: J:183239

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Genetics

Slc12a6^tm1Garo

Allele Symbol: Slc12a6^tm1Garo

Allele Name	targeted mutation 1, Guy A Rouleau
Allele Type	Targeted (Conditional ready (e.g. floxed), No functional change)
Allele Synonym(s)	targeted mutation 1, Guy A Rouleau; Slc12a6^tm1Garo
Gene Symbol and Name	Slc12a6, solute carrier family 12, member 6
Gene Synonym(s)	ACCPN; gaxp; KCC3A; KCC3; KCC3B; gaxp; giant axonopathy; Kcc3
Strain of Origin	129
Chromosome	2
Molecular Note	An FRT and LoxP flanked neo cassette was inserted upstream of exon 18 and a loxP site was inserted downstream of exon 18 via homologous recombination.
Mutations Made By	Guy Rouleau, Universite de Montreal

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).

agenesis of the corpus callosum with peripheral neuropathy

Research Areas By Genotype

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

Research Tools
- Cre-lox System
  - loxP-flanked Sequences
Neurobiology Research
- Cre-lox System
  - loxP-flanked Sequences

Mammalian Phenotype Terms by Genotype

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

Genotype: Slc12a6^tm1Garo/Slc12a6^tm1Garo Tg(Syn1-cre)671Jxm/0
involves: 129 * C57BL/6 * CBA

behavior/neurological phenotype

abnormal locomotor behavior
- deficiencies become more severe after 8 months of age
- severe locomotor deficiencies

decreased chemical nociceptive threshold
- significantly less sensitive in a formalin test of spontaneous chemical/inflammatory pain

hyperactivity
- significant increase in the total distance traveled and the number of movement bouts at 5 months of age

impaired coordination

limb grasping
- by 3-4 weeks of age

reproductive system phenotype

infertility
- unable to successfully breed

growth/size/body region phenotype

decreased body weight
- at 2 months of age

integument phenotype

decreased chemical nociceptive threshold
- significantly less sensitive in a formalin test of spontaneous chemical/inflammatory pain

nervous system phenotype

abnormal axon morphology
- axon swelling in sciatic nerves

abnormal nervous system morphology
- progressive peripheral neuropathy starting at 3-4 weeks of age

abnormal sciatic nerve morphology
- axon degeneration, hypomyelination and axon swelling in sciatic nerves

axon degeneration
- in sciatic nerves

decreased corpus callosum size
- hypoplastic with a small but significant decrease in length

demyelination
- hypomyelination in sciatic nerves

increased brain weight
- at 2 months of age

The following phenotype relates to a compound genotype created using this strain

Genotype: Slc12a6^tm1Garo/Slc12a6^tm1Garo
B6.129-Slc12a6

normal phenotype

no abnormal phenotype detected
- viable and fertile with no signs of neuropathy or motor weakness

References

Shekarabi M; Moldrich RX; Rasheed S; Salin-Cantegrel A; Laganiere J; Rochefort D; Hince P; Huot K; Gaudet R; Kurniawan N; Sotocinal SG; Ritchie J; Dion PA; Mogil JS; Richards LJ; Rouleau GA. 2012. Loss of neuronal potassium/chloride cotransporter 3 (KCC3) is responsible for the degenerative phenotype in a conditional mouse model of hereditary motor and sensory neuropathy associated with agenesis of the corpus callosum. J Neurosci 32(11):3865-76PubMed: 22423107 MGI: J:183239

Additional - Slc12a6^tm1Garo related

Technical Support

Contact Technical Support

Genotyping Protocols
- Separated PCR: Slc12a6^tm1Garo
- Genotyping resources and troubleshooting
Breeding Considerations

While maintaining a live colony, these mice are bred as homozygotes.
- Additional Breeding and Husbandry Support
Citation
When using the B6.129-Slc12a6^tm1Garo/J mouse strain in a publication, please cite the originating article(s) and include JAX stock #018982 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 for Slc12a6<tm1Garo>

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.

Related Products and Services

Frozen Mouse Embryo

$2,595.00 per straw or vial

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Terms are granted by individual review and stated on the customer invoice(s) and account statement. These transactions are payable in U.S. currency within the granted terms. Payment for services, products, shipping containers, and shipping costs that are rendered are expected within the payment terms indicated on the invoice or stated by contract. Invoices and account balances in arrears of stated terms may result in The Jackson Laboratory pursuing collection activities including but not limited to outside agencies and court filings.

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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.

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Licensing Information

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Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Approximate Controls

Additional Information

Selected References

Slc12a6tm1Garo

Allele Symbol: Slc12a6tm1Garo

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: Slc12a6tm1Garo/Slc12a6tm1Garo Tg(Syn1-cre)671Jxm/0involves: 129 * C57BL/6 * CBA

behavior/neurological phenotype

reproductive system phenotype

growth/size/body region phenotype

integument phenotype

nervous system phenotype

Genotype: Slc12a6tm1Garo/Slc12a6tm1GaroB6.129-Slc12a6

normal phenotype

References

Additional - Slc12a6tm1Garo 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

Licensing Information

JAX® Mice, Products & Services Conditions of Use

No Warranty

Credit for PRODUCTS or SERVICES

Animal Care and Use for SERVICES

No Liability

Slc12a6^tm1Garo

Allele Symbol: Slc12a6^tm1Garo

Genotype: Slc12a6^tm1Garo/Slc12a6^tm1Garo Tg(Syn1-cre)671Jxm/0
involves: 129 * C57BL/6 * CBA

Genotype: Slc12a6^tm1Garo/Slc12a6^tm1Garo
B6.129-Slc12a6

Additional - Slc12a6^tm1Garo related