Overview

Also Known As:Vapb^P56S knock-in

The Vapb^P56S knock-in allele has the endogenous Vapb exon 2 replaced by a mutant encoding the P56S amino acid change associated with human amyotrophic lateral sclerosis 8 (ALS8). Homozygotes exhibit several characteristics of the human disease, including cellular pathological features (accumulation of ubiquitinated proteins, ER stress and autophagic response) that are followed by late-onset motor behavior defects. Heterozygotes are less severe; showing mild age-dependent defects in motor behaviors.

Donating Investigator

Hiroshi Tsuda, McGill University

Genetic overview

Genetic Background	Generation

Vapb^tm1.1Tsud

Allele Type	Gene Symbol	Gene Name
Targeted (Humanized sequence)	Vapb	vesicle-associated membrane protein, associated protein B and C

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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

The Vapb^P56S knock-in allele has the P56S mutation associated with human amyotrophic lateral sclerosis 8 (ALS8) inserted into exon 2 of the vesicle-associated membrane protein-associated protein B and C locus (Vapb).
Homozygous mice (Vapb^P56S/P56S) exhibit a slowly progressive motor neuron disease with cellular pathological features prior to late-onset motor behavior defects; characteristic of the human ALS8 / spinal muscular atrophy (SMA) associated with VAPB^P56S. Specifically, the homozygous cellular pathology is accumulation of VAPB^P56S and ubiquitinated proteins in cytoplasmic inclusions (selectively in motor neurons), as well as induction of ER stress and autophagic response in motor neurons.
Heterozygous mice (Vapb^P56S/+) are less severe; showing mild age-dependent defects in motor behaviors as characteristic features of the disease.
Both heterozygous and homozygous mice are viable and fertile, with normal Mendelian distribution.
The Vapb^P56S knock-in allele is transcribed at comparable levels to those of the endogenous Vapb gene, but the P56S mutation renders the VAPB^P56S protein detergent-insoluble.

The Vapb^P56S knock-in mice were first published/characterized on the 129SvEv genetic background in 2015, and this phenotype is described above. It should be noted that the phenotype of the C57BL/6-congenic Vapb^P56S knock-in mice could vary from that originally described on a 129SvEv genetic background. However, the donating investigator reports that Vapb^P56S knock-in mice on the C57BL/6 background and Vapb^P56S knock-in mice on the 129SvEv background show the same cellular biological defects; including VAPB positive inclusion and accumulation of ubiquitinated proteins.

Development

The Vapb^P56S knock-in mutation was designed by Dr. Hiroshi Tsuda (McGill University) to have exon 2 of the vesicle-associated membrane protein-associated protein B and C gene (Vapb; ALS8) on chromosome 2 replaced with the P56S mutant Vapb (Vapb^P56S) exon 2 and a loxP-flanked PGK-neo cassette. The targeting vector was electroporated into 129S7/SvEvBrd-Hprt^b-m2-derived AB2.2 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts. Chimeric males were bred to 129S7/SvEv females for germline transmission. The donating investigator reports that mice were bred with CMV-Cre mice (Hprt^{tm1(CMV-cre)Brd}; 129S7/SvEv genetic background) for germline deletion of the PGK-neo cassette. The resulting Vapb^P56S colony was maintained by breeding heterozygous males with C57BL/6J females for at least eight generations, and then by several years of homozygous matings. In 2015, homozygous males were sent to The Jackson Laboratory Repository. Upon arrival, sperm was cryopreserved. To establish our live colony, an aliquot of frozen sperm was used to fertilize C57BL/6J oocytes (Stock No. 000664).

Of note, the donating investigator reports that prior to sending to The Jackson Laboratory, the Y chromosome may not have been fixed to the C57BL/6J background during backcrossing.

Control Suggestions

Wild-type from the colony
000664 C57BL/6J

Additional Information

Considerations for Choosing Controls

Selected References

Larroquette F; Seto L; Gaub PL; Kamal B; Wallis D; Lariviere R; Vallee J; Robitaille R; Tsuda H. 2015. Vapb/Amyotrophic lateral sclerosis 8 knock-in mice display slowly progressive motor behavior defects accompanying ER stress and autophagic response. Hum Mol Genet 24(22):6515-29PubMed: 26362257 MGI: J:226459

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Genetics

Vapb^tm1.1Tsud

Allele Symbol: Vapb^tm1.1Tsud

Allele Name	targeted mutation 1.1, Hiroshi Tsuda
Allele Type	Targeted (Humanized sequence)
Allele Synonym(s)	Vapb^P56S
Gene Symbol and Name	Vapb, vesicle-associated membrane protein, associated protein B and C
Gene Synonym(s)
Strain of Origin	129S7/SvEvBrd-Hprt^b-m2
Chromosome	2
Molecular Note	The targeting vector is designed to replace exon 2 of the gene with the an altered exon 2 carrying a P56S (proline to serine) missense mutation and a loxP-flanked PGK-neo cassette. Cre-mediated recombination removed the floxed neo cassette.

Disease/Phenotype

Disease Terms

Research Areas By Phenotype

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

Research Tools
- Neurobiology Research
Neurobiology Research
- Spinal Muscular Atrophy (SMA)
- Neuromuscular defects
- Ataxia (Movement) Defects
- Amyotrophic Lateral Sclerosis (ALS)
- Neurodegeneration

Mammalian Phenotype Terms by Genotype

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

Genotype: Vapb^tm1.1Tsud/Vapb^tm1.1Tsud
involves: 129S7/SvEvBrd

behavior/neurological phenotype

impaired coordination
- decrease in latency to fall in rotarod test beginning at 15 months of age
- progressive decrease in latency to fall in inverted grid test beginning at 11 months of age; phenotype is more severe in homozygotes than in heterozygotes

muscle phenotype

centrally nucleated skeletal muscle fibers
- increased number of internal nuclei in muscle fibers

skeletal muscle fiber atrophy
- atrophic cells found in soleus muscle

nervous system phenotype

abnormal neuromuscular synapse morphology
- post-synaptic area of neuromuscular junction has a fragmented appearance; phenotype is more severe in homozygotes than in heterozygotes
- total endplate area is increased in size

abnormal synaptic bouton morphology
- homozygote phenotype is more severe than heterozygote phenotype
- increase in number of pre-synaptic boutons, although size of boutons is similar to controls

axon degeneration
- mice exhibit mild denervation of lower motor neurons

neuronal cytoplasmic inclusions
- increased number of inclusions are observed in homozygous mice as compared to heterozygous mice
- motor neurons of the spinal cord exhibit cytoplasmic inclusions containing ubiquitinated proteins at 6 months of age

Genotype: Vapb^tm1.1Tsud/Vapb⁺
involves: 129S7/SvEvBrd

behavior/neurological phenotype

impaired coordination
- decrease in latency to fall in rotarod test beginning at 15 months of age
- progressive decrease in latency to fall in inverted grid test beginning at 11 month of age

nervous system phenotype

abnormal neuromuscular synapse morphology
- post-synaptic area of neuromuscular junction has a fragmented appearance; phenotype is less severe in heterozygotes than in homozygote

abnormal synaptic bouton morphology
- homozygote phenotype is more severe than heterozygote phenotype
- increase in number of pre-synaptic boutons, although size of boutons is similar to controls

axon degeneration
- mice exhibit mild denervation of lower motor neurons; phenotype is less severe in heterozygotes than in homozygote

neuronal cytoplasmic inclusions
- fewer inclusions are observed in heterozygous mice as compared to homozygotes
- motor neurons of the spinal cord exhibit cytoplasmic inclusions containing ubiquitinated proteins at 6 months of age

References

Larroquette F; Seto L; Gaub PL; Kamal B; Wallis D; Lariviere R; Vallee J; Robitaille R; Tsuda H. 2015. Vapb/Amyotrophic lateral sclerosis 8 knock-in mice display slowly progressive motor behavior defects accompanying ER stress and autophagic response. Hum Mol Genet 24(22):6515-29PubMed: 26362257 MGI: J:226459

Additional - Vapb^tm1.1Tsud related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Standard PCR:Vapb-Alternate1
- Sanger sequencing:Vapb-SEQ
- Genotyping resources and troubleshooting
Breeding Considerations

When maintaining a live colony, heterozygotes may be bred together, to wildtype mice from the colony or to C57BL/6J inbred mice (Stock No. 000664). Alternatively, homozygous mice may be bred together.
- Additional Breeding and Husbandry Support
Mating System
- Wild-type x Heterozygote
- Heterozygote x Wild-type
Citation
When using the Vapb^P56S knock-in mouse strain in a publication, please cite the originating article(s) and include JAX stock #028360 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/Product	Description	Price
	Heterozygous or wildtype for Vapb<tm1.1Tsud>

Related Products and Services

Frozen Mouse Embryo	B6.129S7-Vapb<tm1.1Tsud>/J Frozen Embryo	$2595.00
Frozen Mouse Embryo	B6.129S7-Vapb<tm1.1Tsud>/J Frozen Embryo	$2595.00
Frozen Mouse Embryo	B6.129S7-Vapb<tm1.1Tsud>/J Frozen Embryo	$3373.50
Frozen Mouse Embryo	B6.129S7-Vapb<tm1.1Tsud>/J Frozen Embryo	$3373.50

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Also Known As:VapbP56S knock-in

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Additional Information

Selected References

Vapbtm1.1Tsud

Allele Symbol: Vapbtm1.1Tsud

Disease Terms

Research Areas By Phenotype

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

Mammalian Phenotype Terms by Genotype

Genotype: Vapbtm1.1Tsud/Vapbtm1.1Tsudinvolves: 129S7/SvEvBrd

behavior/neurological phenotype

muscle phenotype

nervous system phenotype

Genotype: Vapbtm1.1Tsud/Vapb+involves: 129S7/SvEvBrd

behavior/neurological phenotype

nervous system phenotype

References

Additional - Vapbtm1.1Tsud related

Genotyping Protocols

Breeding Considerations

Mating System

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

Also Known As:Vapb^P56S knock-in

Vapb^tm1.1Tsud

Allele Symbol: Vapb^tm1.1Tsud

Genotype: Vapb^tm1.1Tsud/Vapb^tm1.1Tsud
involves: 129S7/SvEvBrd

Genotype: Vapb^tm1.1Tsud/Vapb⁺
involves: 129S7/SvEvBrd

Additional - Vapb^tm1.1Tsud related