Description

Strain Information

Type Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered Mutant Mice. Species laboratory mouse Generation N1F11N1p (27-MAR-05)   Donating Investigator Richard Myers,   Stanford University School of Medicine

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.

Control Information

	Control
	Wild-type from the colony
Considerations for Choosing Controls

Additional Web Information

New 129 Nomenclature Bulletin

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms

Myoclonic Epilepsy of Unverricht and Lundborg - 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

Cstb^tm1Rm/Cstb^tm1Rm

        either: (involves: 129S1/Sv * 129X1/SvJ) or (involves: 129S1/Sv * 129X1/SvJ * C57BL/6)

• behavior/neurological phenotype
• *normal* behavior/neurological phenotype (MGI Ref ID J:50587)
  • at 1-3 months of age, mutant mice displayed normal grooming behavior, coordination and strength
• abnormal gait (MGI Ref ID J:50587)
  • 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 (MGI Ref ID J:50587)
  • at 6 months, homozygous null mice showed mild signs of ataxia
• impaired coordination (MGI Ref ID J:50587)
  • at 7-9 months of age, mutant mice performed poorly on both the still and rotating rotorod
• myoclonus (MGI Ref ID J:50587)
  • isogenic 129/Sv mutant mice developed myoclonus and seizures during sleep by 1 month of age
  • 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
  • each event lasted from a few seconds to several minutes, and ended with a large myoclonic outburst that catapulted the animal into the air
  • 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
  • electrocortical graph recordings revealed abnormal cortical activity during the stereotyped behavioral seizures; seizure episodes correlated precisely (1:1) with the multifocal myoclonic activity
  • 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
  • isogenic 129/Sv mutant mice exhibited no photoconvulsive response following a 1-45-Hz photic stimulation
  • ECoG recordings from awake homozygotes, or mutant mice on the mixed 129Sv x C57BL/6 genetic background, showed no identifiable cortical seizure patterns
• cellular phenotype
• abnormal apoptosis (MGI Ref ID J:50587)
  • 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
  • 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
• growth/size phenotype
• *normal* growth/size phenotype (MGI Ref ID J:50587)
  • homozygous null mice were viable and appeared phenotypically normal at 3 weeks prior to weaning
  • at 1-3 months of age, mutant mice displayed normal size and weight relative to wild-type
• immune system phenotype
• increased incidence of corneal inflammation (MGI Ref ID J:50587)
  • with increasing age, increased incidence of corneal inflammation was observed in the absence of bacterial or viral infections
• uveitis (MGI Ref ID J:50587)
  • a few corneal opacities were associated with anterior uveitis, i.e. accumulations of neutrophils in the anterior chamber
• muscle phenotype
• myoclonus (MGI Ref ID J:50587)
  • isogenic 129/Sv mutant mice developed myoclonus and seizures during sleep by 1 month of age
  • 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
  • each event lasted from a few seconds to several minutes, and ended with a large myoclonic outburst that catapulted the animal into the air
  • 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
  • electrocortical graph recordings revealed abnormal cortical activity during the stereotyped behavioral seizures; seizure episodes correlated precisely (1:1) with the multifocal myoclonic activity
  • 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
  • isogenic 129/Sv mutant mice exhibited no photoconvulsive response following a 1-45-Hz photic stimulation
  • ECoG recordings from awake homozygotes, or mutant mice on the mixed 129Sv x C57BL/6 genetic background, showed no identifiable cortical seizure patterns
• vision/eye phenotype
• abnormal cornea morphology (MGI Ref ID J:50587)
  • the corneal epithelial layers appeared eroded, ulcerated, or hyperplastic and keratinized
• corneal opacity (MGI Ref ID J:50587)
  • 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 (MGI Ref ID J:50587)
  • with increasing age, increased incidence of corneal inflammation was observed in the absence of bacterial or viral infections
• abnormal eye physiology (MGI Ref ID J:50587)
  • 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
• increased incidence of corneal inflammation (MGI Ref ID J:50587)
  • with increasing age, increased incidence of corneal inflammation was observed in the absence of bacterial or viral infections
• uveitis (MGI Ref ID J:50587)
  • a few corneal opacities were associated with anterior uveitis, i.e. accumulations of neutrophils in the anterior chamber
• nervous system phenotype
• abnormal nervous system physiology (MGI Ref ID J:71823)
  • quantitative RT-PCR revealed significant increases in the transcript levels of several transcripts in neurological tissues from inbred 129X1/SvJ homozygous null mice
• myoclonus (MGI Ref ID J:50587)
  • isogenic 129/Sv mutant mice developed myoclonus and seizures during sleep by 1 month of age
  • 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
  • each event lasted from a few seconds to several minutes, and ended with a large myoclonic outburst that catapulted the animal into the air
  • 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
  • electrocortical graph recordings revealed abnormal cortical activity during the stereotyped behavioral seizures; seizure episodes correlated precisely (1:1) with the multifocal myoclonic activity
  • 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
  • isogenic 129/Sv mutant mice exhibited no photoconvulsive response following a 1-45-Hz photic stimulation
  • ECoG recordings from awake homozygotes, or mutant mice on the mixed 129Sv x C57BL/6 genetic background, showed no identifiable cortical seizure patterns
• cerebellum hypoplasia (MGI Ref ID J:50587)
  • at 6-9 months, older homozygous null mice displayed a reduction in the density of the granule cell layer in the cerebellum

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

Cstb^tm1Rm/Cstb^tm1Rm

        involves: 129S1/Sv * 129X1/SvJ * C57BL/6

• behavior/neurological phenotype
• ataxia (MGI Ref ID J:115694)
  • by 8 months of age, mice display ataxia
• seizures (MGI Ref ID J:115694)
  • occur during both sleep and wakefulness
• myoclonus (MGI Ref ID J:115694)
  • 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 (MGI Ref ID J:115694)
  • baseline cortical activity displays normal low-amplitude desynchronized EEG with intermittent interictal discharges and bilateral electrographic seizure discharges
• abnormal cerebellum morphology (MGI Ref ID J:115694)
  • apoptosis is observed in cerebellum of mutants but not in wild-type brain at 4 months
• abnormal granule neuron (MGI Ref ID J:115694)
  • widespread granule cell apoptosis is observed in mice at 2, 4, and 6 months of age
• seizures (MGI Ref ID J:115694)
  • occur during both sleep and wakefulness
• myoclonus (MGI Ref ID J:115694)
  • 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
• vision/eye phenotype
• abnormal cornea morphology (MGI Ref ID J:115694)
  • at 8 months, around half of mutants may have serous exudate and or corneal lesions in one or both eyes
• corneal scarring (MGI Ref ID J:115694)
  • 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 (MGI Ref ID J:115694)
  • 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

View Research Applications

Research Applications

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

Cstb^tm1Rm related

Neurobiology Research
Ataxia (Movement) Defects
Cerebellar Defects
Epilepsy
Neurodegeneration

Sensorineural Research
Eye Defects

Genes & Alleles

Gene & Allele Information

Allele Symbol		Cstbtm1Rm
Allele Name		targeted mutation 1, Richard M Myers
Allele Type		Targeted (knock-out)
Mutation Made By		Len Pennacchio,   Lawrence Berkeley National Laboratory
Strain of Origin		(129X1/SvJ x 129S1/Sv)F1-Kitl+
ES Cell Line Name		R1
ES Cell Line Strain		(129X1/SvJ x 129S1/Sv)F1-Kitl<+>
Gene Symbol and Name		Cstb, cystatin B
Chromosome		10
Gene Common Name(s)		AA960480; CST6; Cyb; EPM1; MGC105499; PME; STFB; Stfb; expressed sequence AA960480; stefin B (cystatin B);
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. [MGI Ref ID J:50587]

Genotyping

Genotyping Information

Genotyping Protocols

Cstb^tm1Rm, STD PCR, vers. 1

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

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):251-8. [PubMed: 9806543]  [MGI Ref ID J:50587]

Additional References

Cstb^tm1Rm related

Franceschetti S; Sancini G; Buzzi A; Zucchini S; Paradiso B; Magnaghi G; Frassoni C; Chikhladze M; Avanzini G; Simonato M. 2007. A pathogenetic hypothesis of Unverricht-Lundborg disease onset and progression. Neurobiol Dis 25(3):675-85. [PubMed: 17188503]  [MGI Ref ID J:119089]

Houseweart MK; Vilaythong A; Yin XM; Turk B; Noebels JL; Myers RM. 2003. Apoptosis caused by cathepsins does not require Bid signaling in an in vivo model of progressive myoclonus epilepsy (EPM1). Cell Death Differ 10(12):1329-35. [PubMed: 12934064]  [MGI Ref ID J:115694]

Lieuallen K; Pennacchio LA; Park M; Myers RM; Lennon GG. 2001. Cystatin B-deficient mice have increased expression of apoptosis and glial activation genes. Hum Mol Genet 10(18):1867-71. [PubMed: 11555622]  [MGI Ref ID J:71823]

Shannon P; Pennacchio LA; Houseweart MK; Minassian BA; Myers RM. 2002. Neuropathological changes in a mouse model of progressive myoclonus epilepsy: cystatin B deficiency and Unverricht-Lundborg disease. J Neuropathol Exp Neurol 61(12):1085-91. [PubMed: 12484571]  [MGI Ref ID J:104999]

Health & husbandry

Health & Colony Maintenance Information

Colony Maintenance

Diet Information	LabDiet® 5K52/5K67

Purchasing information

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

Pricing

Supply Details

Standard Supply

Repository-Cryopreserved. Must Be Recovered. Please refer to pricing and supply notes for further information.

Supply Notes

Cryorecovery - Standard. The recovery process begins when a signed agreement form is returned to the Customer Service Department after order placement. Although results vary by strain, at least two males and two females (two pairs) will be provided, typically within 15 weeks of our receipt of the signed agreement form. If the first recovery attempt is unsuccessful or only one pair is recovered, a second recovery will be done, extending the delivery time to approximately 25 weeks. At least one member of each pair will be of known genotype and will carry the mutation if it is a mutant strain. Please note that pairs may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation of the strain. Mating schemes are sometimes modified for successful cryopreservation. Price represents a repository maintenance fee, which includes the cost of recovery of the strain from the cryopreservation resource and the periodic replacement of the frozen embryos used for recovery. Cryorecovery to establish a Dedicated Supply for greater quantities of mice. One to two pairs will be recovered to establish a Dedicated Supply of mice. Price by quotation. For more information on Dedicated Supply, please contact JAX® Services, Tel: 1-800-422-6423 or 1-207-288-5845. 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
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

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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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