Overview

Also Known As:Cstb KO

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These Cstb knock-out mice exhibit tonic-clonic seizures, myoclonic seizures and progressive neurological dysfunction, including dementia and ataxia.

Donating Investigator

Dr. Richard M. Myers, Stanford University School of Medicine

Genetic overview

Genetic Background	Generation

Cstb^tm1Rm

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	Cstb	cystatin B

View Genetics

Research Applications

Neurobiology Research
Sensorineural Research

View All Research Applications

Details

Detailed Description

The progressive myoclonus epilepsies (PMEs) types are diseases characterized by tonic-clonic seizures, myoclonic seizures and progressive neurological dysfunction, including dementia and ataxia. Mice lacking cystatin B develop myoclonic seizures and ataxia, similar to symptoms seen in one of these human diseases. Specifically, this mouse is a model of Unverricht-Lundborg disease (EPM1).Strain background has an effect on phenotype.

Development

To disrupt the gene, a Cstb targeting vector containing a 12.3 kb PGK-neo expression cassette was inserted into the EagI site in exon 1. The construct was electroporated into (129X1/SvJ x 129S1/Sv)F1-derived R1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into blastocysts. The resulting chimeric animals were bred to crossed to 129/Sv mice.

Control Suggestions

Wild-type from the colony

Additional Information

Considerations for Choosing Controls

Selected References

Pennacchio LA; Bouley DM; Higgins KM; Scott MP; Noebels JL; Myers RM. 1998. Progressive ataxia, myoclonic epilepsy and cerebellar apoptosis in cystatin B-deficient mice. Nat Genet 20(3):251-8PubMed: 9806543 MGI: J:50587

View All References

Genetics

Cstb^tm1Rm

Allele Symbol: Cstb^tm1Rm

Allele Name	targeted mutation 1, Richard M Myers
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	Cystatin b^-
Gene Symbol and Name	Cstb, cystatin B
Gene Synonym(s)
Strain of Origin	(129X1/SvJ x 129S1/Sv)F1-Kitl⁺
Chromosome	10
Molecular Note	A neomycin selection cassette was inserted into exon 1. Northern blot and RT-PCR analysis on RNA derived from liver of homozygous mice demonstrated that no detectable transcript was produced from this allele. Western blot analysis on extracts of brain tissue derived from homozygous mice confirmed that no detectable encoded protein was made.
Mutations Made By	Dr. Len Pennacchio, Lawrence Berkeley National Laboratory

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).

Unverricht-Lundborg syndrome

Research Areas By Phenotype

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

Genotype: Cstb^tm1Rm related

Neurobiology Research
- Ataxia (Movement) Defects
- Cerebellar Defects
- Epilepsy
- Neurodegeneration
Sensorineural Research
- Eye Defects

Mammalian Phenotype Terms by Genotype

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

Genotype: Cstb^tm1Rm/Cstb^tm1Rm
involves: 129S1/Sv * 129X1/SvJ * C57BL/6

behavior/neurological phenotype

ataxia
- by 8 months of age, mice display ataxia

myoclonus
- mice display frequent spontaneous axial myoclonic jerks at rate of 10-15/hour; head and neck are always involved, with whole body involved in most animals

seizures
- occur during both sleep and wakefulness

vision/eye phenotype

abnormal cornea morphology
- at 8 months, around half of mutants may have serous exudate and or corneal lesions in one or both eyes

corneal scarring
- at 8 months, around half of mutants display a mild eye phenotype with corneal lesions and /or serous exudate in one or both eyes

muscle phenotype

myoclonus
- mice display frequent spontaneous axial myoclonic jerks at rate of 10-15/hour; head and neck are always involved, with whole body involved in most animals

nervous system phenotype

abnormal brain wave pattern
- baseline cortical activity displays normal low-amplitude desynchronized EEG with intermittent interictal discharges and bilateral electrographic seizure discharges

abnormal cerebellar granule cell morphology
- widespread granule cell apoptosis is observed in mice at 2, 4, and 6 months of age

abnormal cerebellum morphology
- apoptosis is observed in cerebellum of mutants but not in wild-type brain at 4 months

myoclonus
- mice display frequent spontaneous axial myoclonic jerks at rate of 10-15/hour; head and neck are always involved, with whole body involved in most animals

seizures
- occur during both sleep and wakefulness

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

Genotype: Cstb^tm1Rm/Cstb^tm1Rm
either: (involves: 129S1/Sv * 129X1/SvJ) or (involves: 129S1/Sv * 129X1/SvJ * C57BL/6)

behavior/neurological phenotype

abnormal gait
- at >6 months, mutant mice walked with a wide-based gait and, upon hindlimb rearing, occasionally fell on their sides, but still displayed normal swimming ability

ataxia
- at 6 months, homozygous null mice showed mild signs of ataxia

impaired coordination
- at 7-9 months of age, mutant mice performed poorly on both the still and rotating rotorod

myoclonus
- after the seizure, animals remained still for several seconds, and finally regained mobility
- during sleep, the entire myoclonic seizure occurred often, sometimes every several minutes; seizures occurred only during sleep
- each event lasted from a few seconds to several minutes, and ended with a large myoclonic outburst that catapulted the animal into the air
- ECoG recordings from awake homozygotes, or mutant mice on the mixed 129Sv x C57BL/6 genetic background, showed no identifiable cortical seizure patterns
- electrocortical graph recordings revealed abnormal cortical activity during the stereotyped behavioral seizures; seizure episodes correlated precisely (1:1) with the multifocal myoclonic activity
- isogenic 129/Sv mutant mice developed myoclonus and seizures during sleep by 1 month of age
- isogenic 129/Sv mutant mice exhibited no photoconvulsive response following a 1-45-Hz photic stimulation
- recordings revealed a bilaterally synchronous 4-6-Hz repetitive spike discharge which coincided with the onset of the hyperkinetic behaviour; ECoG activity reverted to the normal non-spiking pattern upon regaining mobility
- seizure episodes were typified by short twitching of either the whiskers, ears or tail, followed by facial spasms and minor shaking of the torso and limbs
- shaking became more prominent with intermittent lightning-like muscle jerks, sometimes propelling the animal forward

cellular phenotype

abnormal apoptosis
- at 3 months, TEM analysis of cerebellar tissue from pure 129X1/SvJ homozygous null mice revealed that granule cells showed both early apoptotic cellular features, including chromatin marginization and nuclear condensation, and late apoptotic cellular features, including the presence of apoptotic bodies and cytoplasmic vacuoles
- in addition to the decreased density of granule cells, all homozygotes contained numerous TUNEL-positive apoptotic cells in the granule cell layer of the cerebellum, regardless of their age
- notably, the cerebellum of pure 129X1/SvJ mutant mice contained ~2-fold more TUNEL-positive granule cells than age-matched mutants derived from the mixed 129Sv x C57BL/6 genetic background
- ures, including the presence of apoptotic bodies and cytoplasmic vacuoles

immune system phenotype

increased incidence of corneal inflammation
- with increasing age, increased incidence of corneal inflammation was observed in the absence of bacterial or viral infections

uveitis
- a few corneal opacities were associated with anterior uveitis, i.e. accumulations of neutrophils in the anterior chamber

mammalian phenotype

behavior/neurological phenotype
- Normal - at 1-3 months of age, mutant mice displayed normal grooming behavior, coordination and strength

growth/size/body region phenotype
- Normal - at 1-3 months of age, mutant mice displayed normal size and weight relative to wild-type
- Normal - homozygous null mice were viable and appeared phenotypically normal at 3 weeks prior to weaning

muscle phenotype

facial muscle spasm

myoclonus
- after the seizure, animals remained still for several seconds, and finally regained mobility
- during sleep, the entire myoclonic seizure occurred often, sometimes every several minutes; seizures occurred only during sleep
- each event lasted from a few seconds to several minutes, and ended with a large myoclonic outburst that catapulted the animal into the air
- ECoG recordings from awake homozygotes, or mutant mice on the mixed 129Sv x C57BL/6 genetic background, showed no identifiable cortical seizure patterns
- electrocortical graph recordings revealed abnormal cortical activity during the stereotyped behavioral seizures; seizure episodes correlated precisely (1:1) with the multifocal myoclonic activity
- isogenic 129/Sv mutant mice developed myoclonus and seizures during sleep by 1 month of age
- isogenic 129/Sv mutant mice exhibited no photoconvulsive response following a 1-45-Hz photic stimulation
- recordings revealed a bilaterally synchronous 4-6-Hz repetitive spike discharge which coincided with the onset of the hyperkinetic behaviour; ECoG activity reverted to the normal non-spiking pattern upon regaining mobility
- seizure episodes were typified by short twitching of either the whiskers, ears or tail, followed by facial spasms and minor shaking of the torso and limbs
- shaking became more prominent with intermittent lightning-like muscle jerks, sometimes propelling the animal forward

nervous system phenotype

abnormal nervous system physiology
- quantitative RT-PCR revealed significant increases in the transcript levels of several transcripts in neurological tissues from inbred 129X1/SvJ homozygous null mice

cerebellum hypoplasia
- at 6-9 months, older homozygous null mice displayed a reduction in the density of the granule cell layer in the cerebellum

myoclonus
- after the seizure, animals remained still for several seconds, and finally regained mobility
- during sleep, the entire myoclonic seizure occurred often, sometimes every several minutes; seizures occurred only during sleep
- each event lasted from a few seconds to several minutes, and ended with a large myoclonic outburst that catapulted the animal into the air
- ECoG recordings from awake homozygotes, or mutant mice on the mixed 129Sv x C57BL/6 genetic background, showed no identifiable cortical seizure patterns
- electrocortical graph recordings revealed abnormal cortical activity during the stereotyped behavioral seizures; seizure episodes correlated precisely (1:1) with the multifocal myoclonic activity
- isogenic 129/Sv mutant mice developed myoclonus and seizures during sleep by 1 month of age
- isogenic 129/Sv mutant mice exhibited no photoconvulsive response following a 1-45-Hz photic stimulation
- recordings revealed a bilaterally synchronous 4-6-Hz repetitive spike discharge which coincided with the onset of the hyperkinetic behaviour; ECoG activity reverted to the normal non-spiking pattern upon regaining mobility
- seizure episodes were typified by short twitching of either the whiskers, ears or tail, followed by facial spasms and minor shaking of the torso and limbs
- shaking became more prominent with intermittent lightning-like muscle jerks, sometimes propelling the animal forward

vision/eye phenotype

abnormal cornea morphology
- the corneal epithelial layers appeared eroded, ulcerated, or hyperplastic and keratinized

abnormal eye physiology
- at 1-3 months of age, approximately 40% of homozygous null mice displayed narrowed palpebral fissures (squinting), increased lacrimation (tearing) and periocular buildup of serous to mucoid exudate

corneal opacity
- as homozygous null mice aged from 3 to 7 months, 35% of mutants and 0% of wild-type littermates developed corneal opacity in one or both eyes; in 35% of the cases, both eyes were affected
- corneal opacities corresponded with histopathological lesions of acute to chronic keratitis

increased incidence of corneal inflammation
- with increasing age, increased incidence of corneal inflammation was observed in the absence of bacterial or viral infections

uveitis
- a few corneal opacities were associated with anterior uveitis, i.e. accumulations of neutrophils in the anterior chamber

References

Pennacchio LA; Bouley DM; Higgins KM; Scott MP; Noebels JL; Myers RM. 1998. Progressive ataxia, myoclonic epilepsy and cerebellar apoptosis in cystatin B-deficient mice. Nat Genet 20(3):251-8PubMed: 9806543 MGI: J:50587

Additional - Cstb^tm1Rm related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- Standard PCR:Cstb-alternate2
- Genotyping resources and troubleshooting
Breeding Considerations

While maintaining a live colony, these mice are maintained by homozygote sibling matings.
- Additional Breeding and Husbandry Support
Citation
When using the Cstb KO mouse strain in a publication, please cite the originating article(s) and include JAX stock #003486 in your Materials and Methods section.

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Also Known As:Cstb KO

Donating Investigator

Genetic overview

Research Applications

Detailed Description

Development

Control Suggestions

Additional Information

Selected References

Cstbtm1Rm

Allele Symbol: Cstbtm1Rm

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 Phenotype

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

Genotype: Cstbtm1Rm related

Mammalian Phenotype Terms by Genotype

Genotype: Cstbtm1Rm/Cstbtm1Rminvolves: 129S1/Sv * 129X1/SvJ * C57BL/6

behavior/neurological phenotype

vision/eye phenotype

muscle phenotype

nervous system phenotype

Genotype: Cstbtm1Rm/Cstbtm1Rmeither: (involves: 129S1/Sv * 129X1/SvJ) or (involves: 129S1/Sv * 129X1/SvJ * C57BL/6)

behavior/neurological phenotype

cellular phenotype

immune system phenotype

mammalian phenotype

muscle phenotype

nervous system phenotype

vision/eye phenotype

References

Additional - Cstbtm1Rm related

Genotyping Protocols

Breeding Considerations

Citation

Strain Interest Registration

Contact Information

Interest

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

Cstb^tm1Rm

Allele Symbol: Cstb^tm1Rm

Genotype: Cstb^tm1Rm related

Genotype: Cstb^tm1Rm/Cstb^tm1Rm
involves: 129S1/Sv * 129X1/SvJ * C57BL/6

Genotype: Cstb^tm1Rm/Cstb^tm1Rm
either: (involves: 129S1/Sv * 129X1/SvJ) or (involves: 129S1/Sv * 129X1/SvJ * C57BL/6)

Additional - Cstb^tm1Rm related