Overview

Also Known As:Pcmt1- , PIMT^-

PCMT1 is a protein repair methyltransferase that initiates the conversion of L-isoaspartyl residues to normal L-aspartyl residues. Homozygous deficiency of this isoaspartyl repair methyl-transferase may be useful in studying isoaspartyl accumulation in seizure disorders, cellular-damage induced neurogenesis, aging, the PI3K/Akt signal transduction pathway, the insulin signaling pathway and autophagy/protein turnover.

Donating Investigator

Steven G Clarke, University of California Los Angeles (UCLA)

Genetic overview

Genetic Background	Generation

Pcmt1^tm1Scl

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	Pcmt1	protein-L-isoaspartate (D-aspartate) O-methyltransferase 1

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Research Applications

Cell Biology Research
Cancer Research
Immunology, Inflammation and Autoimmunity Research
Developmental Biology Research
Neurobiology Research
Diabetes and Obesity Research
Research Tools

View All Research Applications

Base Price

Starting at:

$2,854.50 Domestic price Cryo Recovery

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Details

Detailed Description

Heterozygous (Pcmt^+/-) mice are viable and fertile. Homozygous (Pcmt^-/-) mice have significantly increased isoaspartyl residues in intracellular proteins (deficits in the repair of isoaspartyl protein damage), with alterations in the insulin-like growth factor-I pathway and insulin receptor pathway in the brain. Homozygous mice exhibit reduced overall body size, progressive brain enlargement, increased neuronal cell proliferation, and death at approximately 45 days of age from tonic-clonic seizures. The brain enlargement is attributed to aberrantly increased insulin signaling in neuronal tissues. Homozygous Pcmt1-deficiency also increases the ratio of S-adenosylmethionine to S-adenosylhomocysteine by ~2.3-fold in brain tissue at 40 days of age, which likely affects the activity of many of the other cellular methyltransferases. Pcmt^-/- mice also have a mild impairment in glucose tolerance (higher peak levels of blood glucose), but no significant differences in plasma insulin levels, during glucose tolerance tests.

Development

The Pcmt1 knockout allele (Pcmt^-) was designed by Dr. Stephen G. Young (University of California Los Angeles) with a neomycin-resistance cassette inserted into exon 1 (after the sequence encoding the first six amino acids) of the protein carboxyl methyltransferase gene (Pcmt1). The targeting vector was electroporated into 129S4/SvJae-derived RF8 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts. Chimeric mice were bred with C57BL/6 mice to establish the colony. Heterozygous mice (Pcmt^+/-) were bred together for more than fifteen years (genetic background approximately 50% 129/SvJae and 50% C57BL/6) prior to sending males to The Jackson Laboratory Repository in 2013. Upon arrival, males were used to cryopreserve sperm. To establish our living Pcmt^- mouse colony, an aliquot of the frozen sperm was used to fertilize oocytes from C57BL/6J inbred females (Stock No. 000664).

Control Suggestions

Wild-type from the colony

Additional Information

Considerations for Choosing Controls

Selected References

Farrar C; Clarke S. 2002. Altered levels of S-adenosylmethionine and S-adenosylhomocysteine in the brains of L-isoaspartyl (D-Aspartyl) O-methyltransferase-deficient mice. J Biol Chem 277(31):27856-63PubMed: 12023972 MGI: J:78144
Farrar C; Houser CR; Clarke S. 2005. Activation of the PI3K/Akt signal transduction pathway and increased levels of insulin receptor in protein repair-deficient mice. Aging Cell 4(1):1-12PubMed: 15659208 MGI: J:201872
Farrar CE; Huang CS; Clarke SG; Houser CR. 2005. Increased cell proliferation and granule cell number in the dentate gyrus of protein repair-deficient mice. J Comp Neurol 493(4):524-37PubMed: 16304629 MGI: J:104595
Kim E; Lowenson JD; MacLaren DC; Clarke S; Young SG. 1997. Deficiency of a protein-repair enzyme results in the accumulation of altered proteins, retardation of growth, and fatal seizures in mice. Proc Natl Acad Sci U S A 94(12):6132-7PubMed: 9177182 MGI: J:40967
MacKay KB; Lowenson JD; Clarke SG. 2012. Wortmannin reduces insulin signaling and death in seizure-prone Pcmt1-/- mice. PLoS One 7(10):e46719PubMed: 23071621 MGI: J:192091

View All References

Genetics

Pcmt1^tm1Scl

Allele Symbol: Pcmt1^tm1Scl

Allele Name	targeted mutation 1, Steven Clarke
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	Pcmt1-; PIMT^-
Gene Symbol and Name	Pcmt1, protein-L-isoaspartate (D-aspartate) O-methyltransferase 1
Gene Synonym(s)
Strain of Origin	129S4/SvJae
Chromosome	10
Molecular Note	Exon 1 was replaced with a neomycin selection cassette after sequence encoding the first 6 amino acids. Western blot analysis of various tissues and assays of brain, heart, liver, and red blood cells showed that the absence of protein and methyltransferase activity in homozygous mutant mice.

Disease/Phenotype

Disease Terms

Research Areas By Phenotype

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

Cell Biology Research
- DNA Damage Response
- Signal Transduction
- Genes Regulating Growth and Proliferation
- Protein Processing
  - degradation
Cancer Research
- Other
  - DNA Repair
- Genes Regulating Growth and Proliferation
Immunology, Inflammation and Autoimmunity Research
- Intracellular Signaling Molecules
Developmental Biology Research
- Internal/Organ Defects
  - brain
Neurobiology Research
- Cortical Defects
- Epilepsy
Diabetes and Obesity Research
- Insulin Receptors and Growth Factors
Research Tools
- Neurobiology Research

Mammalian Phenotype Terms by Genotype

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

Genotype: Pcmt1^tm1Scl/Pcmt1^tm1Scl
involves: 129S4/SvJae * C57BL/6

behavior/neurological phenotype

increased susceptibility to pharmacologically induced seizures
- in response to a single i.p. injection of metrazol (45 mg/kg), all homozygotes exhibit a major motor seizure, 25% of which are fatal; in contrast, only 2 of 18 heterozygotes exhibit a seizure, neither of which is fatal

tonic-clonic seizures
- 9 of 11 seizures are fatal; 2 of 11 are nonfatal but mice die within min to hrs from another seizure
- homozygotes die of generalized seizures, typified by rhythmic clonic movements, tonic extension, and respiratory arrest

nervous system phenotype

increased susceptibility to pharmacologically induced seizures
- in response to a single i.p. injection of metrazol (45 mg/kg), all homozygotes exhibit a major motor seizure, 25% of which are fatal; in contrast, only 2 of 18 heterozygotes exhibit a seizure, neither of which is fatal

tonic-clonic seizures
- 9 of 11 seizures are fatal; 2 of 11 are nonfatal but mice die within min to hrs from another seizure
- homozygotes die of generalized seizures, typified by rhythmic clonic movements, tonic extension, and respiratory arrest

cellular phenotype

abnormal cell physiology
- deficient protein repair
- at P30-P40, homozygotes show normal plasma levels of damaged asparaginyl/aspartyl residues; however, high levels of altered asparaginyl/aspartyl residues accumulate in the cytosolic fraction of mutant erythrocytes, heart, and liver, and brain, indicating deficient protein repair
- significantly higher levels of damaged residues accumulate in brain cytosolic proteins relative to other tissues

growth/size/body region phenotype

postnatal growth retardation
- at >P20, both male and female homozygotes exhibit growth retardation with significantly reduced body lengths and body mass indices relative to wild-type or heterozygous mice

homeostasis/metabolism phenotype

abnormal homeostasis
- paradoxically, 4- to 5-week-old homozygotes show a ~30% increase in glutamate uptake into synaptosomes relative to wild-type or heterozygous mice, indicating altered glutamate metabolism

mortality/aging

premature death
- all homozygotes die by day P60, with most dying suddenly between P22 and p60 (average day of death is 42 days), in the absence of dehydration, malnourishment, or lethargy
- no significant changes in major organ/tissue histology, blood counts, erythrocyte morphology or electrolyte and chemistry are observed
- only 4 of >75 homozygotes survive beyond P60, with two found dead at P74, one at P90, and one at P100

References

Farrar C; Clarke S. 2002. Altered levels of S-adenosylmethionine and S-adenosylhomocysteine in the brains of L-isoaspartyl (D-Aspartyl) O-methyltransferase-deficient mice. J Biol Chem 277(31):27856-63PubMed: 12023972 MGI: J:78144
Farrar C; Houser CR; Clarke S. 2005. Activation of the PI3K/Akt signal transduction pathway and increased levels of insulin receptor in protein repair-deficient mice. Aging Cell 4(1):1-12PubMed: 15659208 MGI: J:201872
Farrar CE; Huang CS; Clarke SG; Houser CR. 2005. Increased cell proliferation and granule cell number in the dentate gyrus of protein repair-deficient mice. J Comp Neurol 493(4):524-37PubMed: 16304629 MGI: J:104595
Kim E; Lowenson JD; MacLaren DC; Clarke S; Young SG. 1997. Deficiency of a protein-repair enzyme results in the accumulation of altered proteins, retardation of growth, and fatal seizures in mice. Proc Natl Acad Sci U S A 94(12):6132-7PubMed: 9177182 MGI: J:40967
MacKay KB; Lowenson JD; Clarke SG. 2012. Wortmannin reduces insulin signaling and death in seizure-prone Pcmt1-/- mice. PLoS One 7(10):e46719PubMed: 23071621 MGI: J:192091

Additional - Pcmt1^tm1Scl related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
Breeding Considerations

Homozygous mice die at approximately 45 days of age from tonic-clonic seizures. When maintaining a live colony, heterozygous mice may be bred together or with wildtype mice from the colony.
- Additional Breeding and Husbandry Support
Citation
When using the Pcmt1- mouse strain in a publication, please cite the originating article(s) and include JAX stock #023343 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 Pcmt1<tm1Scl>

Related Products and Services

Frozen Mouse Embryo	B6;129S4-Pcmt1<tm1Scl>/J Frozen Embryo	$2595.00
Frozen Mouse Embryo	B6;129S4-Pcmt1<tm1Scl>/J Frozen Embryo	$2595.00
Frozen Mouse Embryo	B6;129S4-Pcmt1<tm1Scl>/J Frozen Embryo	$3373.50
Frozen Mouse Embryo	B6;129S4-Pcmt1<tm1Scl>/J Frozen Embryo	$3373.50

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The Jackson Laboratory's Genotype Promise

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. We do not guarantee breeding performance and therefore suggest that investigators order more than one breeding pair to avoid delays in their research.

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General Terms and Conditions

Questions about Terms of Use

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Licensing Information

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Also Known As:Pcmt1- , PIMT-

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Additional Information

Selected References

Pcmt1tm1Scl

Allele Symbol: Pcmt1tm1Scl

Disease Terms

Research Areas By Phenotype

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

Mammalian Phenotype Terms by Genotype

Genotype: Pcmt1tm1Scl/Pcmt1tm1Sclinvolves: 129S4/SvJae * C57BL/6

behavior/neurological phenotype

nervous system phenotype

cellular phenotype

growth/size/body region phenotype

homeostasis/metabolism phenotype

mortality/aging

References

Additional - Pcmt1tm1Scl 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

Also Known As:Pcmt1- , PIMT^-

Pcmt1^tm1Scl

Allele Symbol: Pcmt1^tm1Scl

Genotype: Pcmt1^tm1Scl/Pcmt1^tm1Scl
involves: 129S4/SvJae * C57BL/6

Additional - Pcmt1^tm1Scl related