Strain Name:

B6N.129(C)-Mthfrtm1Rzn/J

Stock Number:

024316

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Availability:

Cryopreserved - Ready for recovery

Mthfr KO mice may be useful for studying DNA methylation control.

Description

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Strain Information

Type Congenic; Mutant Strain; Targeted Mutation;
Additional information on Genetically Engineered and Mutant Mice.
Visit our online Nomenclature tutorial.
Additional information on Congenic nomenclature.
Mating SystemHeterozygote x Heterozygote         (Female x Male)   11-FEB-14
Specieslaboratory mouse
 
Donating Investigator Rima Rozen,   McGill University Health Centre

Description
Mthfr KO mice have a neo cassette disrupting exon 3 of the 5,10-methylenetetrahydrofolate reductase (Mthfr) gene, abolishing gene expression. MTHFR is the rate-limiting enzyme in the methyl cycle. It is involved in the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, which is a cosubstrate for homocysteine remethylation to methionine. Homozygous KO of MTHFR causes an abnormally high level of homocysteine in blood and urine, called hyperhomocysteinemia. Patients with this disorder exhibit developmental delay, thrombosis, motor and gait dysfunction, seizures, and other neurological symptoms. Mild MTHFR deficiency due to polymorphic variation causes a more modest elevation of plasma homocysteine (mild hyperhomocysteinemia), which is associated with increased risk for some common multifactorial disorders. Homozygous Mthfr KO mice exhibit motor and behavioral anomalies, memory impairment, and liver steatosis. Homozygous KO males have normal fertility and relatively normal viability (~80%). These mice on a C57BL/6 background have a milder phenotype than on a BALB/cJ background (Stock No. 024503), although mice on both backgrounds exhibit a 10 fold increase in plasma homocysteine levels.

Development
A targeting vector was designed to insert a neomycin resistance (neo) cassette, in reverse orientation, into exon 3 of the 5,10-methylenetetrahydrofolate reductase (Mthfr) gene. The construct was electroporated into (129X1/SvJ x 129S1/Sv)F1-Kitl+-derived R1 embryonic stem (ES) cells. Correctly targeted ES cells were injected into BALB/c blastocysts and the resulting chimeric males were bred to BALB/cAnCrlBR females. These mice were backcrossed to BALB/cAnCrlBR mice for at least 10 generations, and subsequently they were bred to C57BL/6NCrl mice for at least 10 generations. Upon arrival at The Jackson Laboratory, mice were bred to C57BL/6NJ (Stock No. 005304) for at least one generation to establish the colony.

Control Information

  Control
   005304 C57BL/6NJ (approximate)
 
  Considerations for Choosing Controls

Related Strains

Strains carrying   Mthfrtm1Rzn allele
024503   C.129-Mthfrtm1Rzn/J
View Strains carrying   Mthfrtm1Rzn     (1 strain)

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI
- 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).
Neural Tube Defects, Folate-Sensitive
Models with phenotypic similarity to human diseases where etiology is unknown or involving genes where ortholog is unknown.
Homocysteinemia
- Potential model based on gene homology relationships. Phenotypic similarity to the human disease has not been tested.
Homocystinuria Due to Deficiency of N(5,10)-Methylenetetrahydrofolate Reductase Activity   (MTHFR)
Schizophrenia; SCZD   (MTHFR)
Thrombophilia Due to Thrombin Defect; THPH1   (MTHFR)
View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI
      assigned by genotype

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

Mthfrtm1Rzn/Mthfr+

        involves: 129S1/Sv * 129X1/SvJ * BALB/c
  • homeostasis/metabolism phenotype
  • abnormal circulating homocysteine level   (MGI Ref ID J:67779)
  • abnormal lipid homeostasis
    • lipid accumulation in the aorta near the aortic valve but no foam cells   (MGI Ref ID J:67779)
    • some microvesicular steatosis in the liver   (MGI Ref ID J:67779)

Mthfrtm1Rzn/Mthfr+

        involves: 129S1/Sv * 129X1/SvJ * BALB/cAnNCrl
  • homeostasis/metabolism phenotype
  • abnormal circulating homocysteine level
    • plasma N-homocysteine levels are higher than in wild-type mice   (MGI Ref ID J:150548)

Mthfrtm1Rzn/Mthfrtm1Rzn

        involves: 129S1/Sv * 129X1/SvJ * BALB/c
  • mortality/aging
  • premature death
    • 76.4% survived past 5 weeks of age   (MGI Ref ID J:67779)
  • growth/size/body phenotype
  • decreased body weight   (MGI Ref ID J:67779)
  • postnatal growth retardation
    • slower development than normal   (MGI Ref ID J:67779)
  • homeostasis/metabolism phenotype
  • abnormal circulating homocysteine level   (MGI Ref ID J:67779)
  • abnormal lipid homeostasis
    • lipid accumulation in the aorta near the aortic valve but no foam cells   (MGI Ref ID J:67779)
    • some microvesicular steatosis in the liver   (MGI Ref ID J:67779)
  • limbs/digits/tail phenotype
  • kinked tail
    • sometimes   (MGI Ref ID J:67779)
  • short tail   (MGI Ref ID J:67779)
  • reproductive system phenotype
  • delayed sexual maturation
    • delayed maturation of external genitalia but generally fertile   (MGI Ref ID J:67779)
  • skeleton phenotype
  • kyphosis
    • occasionally   (MGI Ref ID J:67779)
  • vision/eye phenotype
  • exophthalmos
    • among other facial anomalies   (MGI Ref ID J:67779)
  • nervous system phenotype
  • abnormal cerebellar granule layer morphology
  • delaminated Purkinje cell layer
    • intermingled with granule cells rather than forming a discrete layer   (MGI Ref ID J:67779)
  • small cerebellum
    • as determined in sagittal sections   (MGI Ref ID J:67779)
  • integument phenotype
  • sparse hair
    • delayed about 5 days in appearance   (MGI Ref ID J:67779)

Mthfrtm1Rzn/Mthfrtm1Rzn

        involves: 129S1/Sv * 129X1/SvJ * BALB/cAnNCrl
  • homeostasis/metabolism phenotype
  • *normal* homeostasis/metabolism phenotype
    • N-homocysteine levels are normal in the liver and heart and total homocysteine levels are normal in the liver   (MGI Ref ID J:150548)
    • abnormal circulating homocysteine level
      • plasma N-homocysteine levels are higher than in heterozygous or wild-type mice   (MGI Ref ID J:150548)
      • total plasma homocysteine level is mildly elevated compared to in heterozygous and wild-type mice   (MGI Ref ID J:150548)

Mthfrtm1Rzn/Mthfrtm1Rzn

        involves: 129S1/Sv * 129X1/SvJ
  • homeostasis/metabolism phenotype
  • abnormal blood homeostasis
    • increase in plasma cystathionine levels   (MGI Ref ID J:165612)
    • abnormal circulating homocysteine level
      • increase in plasma total homocysteine levels   (MGI Ref ID J:165612)
View Research Applications

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

Cell Biology Research

Metabolism Research
Enzyme Deficiency

Neurobiology Research
Behavioral and Learning Defects

Genes & Alleles

Gene & Allele Information provided by MGI

 
Allele Symbol Mthfrtm1Rzn
Allele Name targeted mutation 1, Rima Rozen
Allele Type Targeted (Null/Knockout)
Common Name(s) Mthfr-;
Strain of Origin(129X1/SvJ x 129S1/Sv)F1-Kitl<+>
Gene Symbol and Name Mthfr, 5,10-methylenetetrahydrofolate reductase
Chromosome 4
Gene Common Name(s) AI323986; expressed sequence AI323986;
Molecular Note Exon 3 was disrupted by the insertion of a neomycin selection cassette. Transcript was undetected by RT-PCR analysis of brain tissue obtained from homozygous mutant mice. Enzymatic activity assays showed a lack of activity in homozygous mutant mice and levels reduced to 60 to 70% of wild-type in heterozygotes. [MGI Ref ID J:67779]

Genotyping

Genotyping Information

Genotyping Protocols

Mthfrtm1Rzn, Standard PCR


Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Chen Z; Karaplis AC; Ackerman SL; Pogribny IP; Melnyk S; Lussier-Cacan S; Chen MF; Pai A; John SW; Smith RS; Bottiglieri T; Bagley P; Selhub J; Rudnicki MA; James SJ; Rozen R. 2001. Mice deficient in methylenetetrahydrofolate reductase exhibit hyperhomocysteinemia and decreased methylation capacity, with neuropathology and aortic lipid deposition. Hum Mol Genet 10(5):433-43. [PubMed: 11181567]  [MGI Ref ID J:67779]

Additional References

Mthfrtm1Rzn related

Chan D; Cushnie DW; Neaga OR; Lawrance AK; Rozen R; Trasler JM. 2010. Strain-specific defects in testicular development and sperm epigenetic patterns in 5,10-methylenetetrahydrofolate reductase-deficient mice. Endocrinology 151(7):3363-73. [PubMed: 20444942]  [MGI Ref ID J:169509]

Chen Z; Schwahn BC; Wu Q; He X; Rozen R. 2005. Postnatal cerebellar defects in mice deficient in methylenetetrahydrofolate reductase. Int J Dev Neurosci 23(5):465-74. [PubMed: 15979267]  [MGI Ref ID J:100044]

Chew TW; Jiang X; Yan J; Wang W; Lusa AL; Carrier BJ; West AA; Malysheva OV; Brenna JT; Gregory JF 3rd; Caudill MA. 2011. Folate intake, mthfr genotype, and sex modulate choline metabolism in mice. J Nutr 141(8):1475-81. [PubMed: 21697299]  [MGI Ref ID J:173752]

Devlin AM; Arning E; Bottiglieri T; Faraci FM; Rozen R; Lentz SR. 2004. Effect of Mthfr genotype on diet-induced hyperhomocysteinemia and vascular function in mice. Blood 103(7):2624-9. [PubMed: 14630804]  [MGI Ref ID J:89039]

Garcia-Crespo D; Knock E; Jabado N; Rozen R. 2009. Intestinal neoplasia induced by low dietary folate is associated with altered tumor expression profiles and decreased apoptosis in mouse normal intestine. J Nutr 139(3):488-94. [PubMed: 19176749]  [MGI Ref ID J:146287]

Garner JL; Niles KM; McGraw S; Yeh JR; Cushnie DW; Hermo L; Nagano MC; Trasler JM. 2013. Stability of DNA methylation patterns in mouse spermatogonia under conditions of MTHFR deficiency and methionine supplementation. Biol Reprod 89(5):125. [PubMed: 24048573]  [MGI Ref ID J:204010]

Ghandour H; Chen Z; Selhub J; Rozen R. 2004. Mice deficient in methylenetetrahydrofolate reductase exhibit tissue-specific distribution of folates. J Nutr 134(11):2975-8. [PubMed: 15514261]  [MGI Ref ID J:102203]

Hoffmann L; Brauers G; Gehrmann T; Haussinger D; Mayatepek E; Schliess F; Schwahn BC. 2013. Osmotic regulation of hepatic betaine metabolism. Am J Physiol Gastrointest Liver Physiol 304(9):G835-46. [PubMed: 23449672]  [MGI Ref ID J:196380]

Jadavji NM; Deng L; Leclerc D; Malysheva O; Bedell BJ; Caudill MA; Rozen R. 2012. Severe methylenetetrahydrofolate reductase deficiency in mice results in behavioral anomalies with morphological and biochemical changes in hippocampus. Mol Genet Metab 106(2):149-59. [PubMed: 22521626]  [MGI Ref ID J:184437]

Jakubowski H; Perla-Kajan J; Finnell RH; Cabrera RM; Wang H; Gupta S; Kruger WD; Kraus JP; Shih DM. 2009. Genetic or nutritional disorders in homocysteine or folate metabolism increase protein N-homocysteinylation in mice. FASEB J 23(6):1721-7. [PubMed: 19204075]  [MGI Ref ID J:150548]

Kelly TL; Neaga OR; Schwahn BC; Rozen R; Trasler JM. 2005. Infertility in 5,10-methylenetetrahydrofolate reductase (MTHFR)-deficient male mice is partially alleviated by lifetime dietary betaine supplementation. Biol Reprod 72(3):667-77. [PubMed: 15548731]  [MGI Ref ID J:104636]

Kezurer N; Galron D; Golan HM. 2013. Increased susceptibility to mild neonatal stress in MTHFR deficient mice. Behav Brain Res 253:240-52. [PubMed: 23896051]  [MGI Ref ID J:202104]

Knock E; Deng L; Wu Q; Lawrance AK; Wang XL; Rozen R. 2008. Strain differences in mice highlight the role of DNA damage in neoplasia induced by low dietary folate. J Nutr 138(4):653-8. [PubMed: 18356316]  [MGI Ref ID J:138499]

Knock E; Deng L; Wu Q; Leclerc D; Wang XL; Rozen R. 2006. Low dietary folate initiates intestinal tumors in mice, with altered expression of G2-M checkpoint regulators polo-like kinase 1 and cell division cycle 25c. Cancer Res 66(21):10349-56. [PubMed: 17079455]  [MGI Ref ID J:114921]

Kvajo M; McKellar H; Gogos JA. 2012. Avoiding mouse traps in schizophrenia genetics: lessons and promises from current and emerging mouse models. Neuroscience 211:136-64. [PubMed: 21821099]  [MGI Ref ID J:184660]

Lemarie CA; Shbat L; Marchesi C; Angulo OJ; Deschenes ME; Blostein MD; Paradis P; Schiffrin EL. 2011. Mthfr deficiency induces endothelial progenitor cell senescence via uncoupling of eNOS and downregulation of SIRT1. Am J Physiol Heart Circ Physiol 300(3):H745-53. [PubMed: 21169404]  [MGI Ref ID J:170362]

Levav-Rabkin T; Blumkin E; Galron D; Golan HM. 2011. Sex-dependent behavioral effects of Mthfr deficiency and neonatal GABA potentiation in mice. Behav Brain Res 216(2):505-13. [PubMed: 20813139]  [MGI Ref ID J:166168]

Li D; Pickell L; Liu Y; Rozen R. 2006. Impact of methylenetetrahydrofolate reductase deficiency and low dietary folate on the development of neural tube defects in splotch mice. Birth Defects Res A Clin Mol Teratol 76(1):55-9. [PubMed: 16397891]  [MGI Ref ID J:112763]

Li D; Rozen R. 2006. Maternal folate deficiency affects proliferation, but not apoptosis, in embryonic mouse heart. J Nutr 136(7):1774-8. [PubMed: 16772436]  [MGI Ref ID J:115049]

Maclean KN; Sikora J; Kozich V; Jiang H; Greiner LS; Kraus E; Krijt J; Overdier KH; Collard R; Brodsky GL; Meltesen L; Crnic LS; Allen RH; Stabler SP; Elleder M; Rozen R; Patterson D; Kraus JP. 2010. A novel transgenic mouse model of CBS-deficient homocystinuria does not incur hepatic steatosis or fibrosis and exhibits a hypercoagulative phenotype that is ameliorated by betaine treatment. Mol Genet Metab 101(2-3):153-62. [PubMed: 20638879]  [MGI Ref ID J:165612]

Mikael LG; Pancer J; Wu Q; Rozen R. 2012. Disturbed one-carbon metabolism causing adverse reproductive outcomes in mice is associated with altered expression of apolipoprotein AI and inflammatory mediators PPARalpha, interferon-gamma, and interleukin-10. J Nutr 142(3):411-8. [PubMed: 22259189]  [MGI Ref ID J:181924]

Mikael LG; Wang XL; Wu Q; Jiang H; Maclean KN; Rozen R. 2009. Hyperhomocysteinemia is associated with hypertriglyceridemia in mice with methylenetetrahydrofolate reductase deficiency. Mol Genet Metab 98(1-2):187-94. [PubMed: 19560954]  [MGI Ref ID J:152562]

Neves MF; Endemann D; Amiri F; Virdis A; Pu Q; Rozen R; Schiffrin EL. 2004. Small artery mechanics in hyperhomocysteinemic mice: effects of angiotensin II. J Hypertens 22(5):959-66. [PubMed: 15097236]  [MGI Ref ID J:105560]

Schwahn BC; Chen Z; Laryea MD; Wendel U; Lussier-Cacan S; Genest J Jr; Mar MH; Zeisel SH; Castro C; Garrow T; Rozen R. 2003. Homocysteine-betaine interactions in a murine model of 5,10-methylenetetrahydrofolate reductase deficiency. FASEB J 17(3):512-4. [PubMed: 12551843]  [MGI Ref ID J:118489]

Schwahn BC; Laryea MD; Chen Z; Melnyk S; Pogribny I; Garrow T; James SJ; Rozen R. 2004. Betaine rescue of an animal model with methylenetetrahydrofolate reductase deficiency. Biochem J 382(Pt 3):831-40. [PubMed: 15217352]  [MGI Ref ID J:93942]

Virdis A; Iglarz M; Neves MF; Amiri F; Touyz RM; Rozen R; Schiffrin EL. 2003. Effect of hyperhomocystinemia and hypertension on endothelial function in methylenetetrahydrofolate reductase-deficient mice. Arterioscler Thromb Vasc Biol 23(8):1352-7. [PubMed: 12829522]  [MGI Ref ID J:103033]

Wlodarczyk BJ; Zhu H; Finnell RH. 2014. Mthfr gene ablation enhances susceptibility to arsenic prenatal toxicity. Toxicol Appl Pharmacol 275(1):22-7. [PubMed: 24384392]  [MGI Ref ID J:205587]

Health & husbandry

The genotypes of the animals provided may not reflect those discussed in the strain description or the mating scheme utilized by The Jackson Laboratory prior to cryopreservation. Please inquire for possible genotypes for this specific strain.

Health & Colony Maintenance Information

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, G200.

Colony Maintenance

Breeding & HusbandryWhen maintaining a live colony, homozygotes may be bred together. Homozygous males exhibit ~80% viability.
Mating SystemHeterozygote x Heterozygote         (Female x Male)   11-FEB-14

Pricing and Purchasing

Pricing, Supply Level & Notes, Controls


Pricing for USA, Canada and Mexico shipping destinations View International Pricing

Cryopreserved

Cryopreserved Mice - Ready for Recovery

Price (US dollars $)
Cryorecovery* $2140.00
Animals Provided

At least two mice that carry the mutation (if it is a mutant strain) will be provided. Their genotypes may not reflect those discussed in the strain description. Please inquire for possible genotypes and see additional details below.

Standard Supply

Cryopreserved. Ready for recovery. Please refer to pricing and supply notes on the strain data sheet for further information.

Supply Notes

  • Cryorecovery - Standard.
    Progeny testing is not required.

    The average number of mice provided from recovery of our cryopreserved strains is 10. The total number of animals provided, their gender and genotype will vary. We will fulfill your order by providing at least two pair of mice, at least one animal of each pair carrying the mutation of interest. Please inquire if larger numbers of animals with specific genotype and genders are needed. Animals typically ship between 10 and 14 weeks from the date of your order. If a second cryorecovery is needed in order to provide the minimum number of animals, animals will ship within 25 weeks. IMPORTANT NOTE: The genotypes of animals provided may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation, or that discussed in the strain description. Please inquire about possible genotypes which will be recovered for this specific strain. The Jackson Laboratory 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. For more information on Dedicated Supply, please contact JAX® Services, Tel: 1-800-422-6423 (from U.S.A., Canada or Puerto Rico only) or 1-207-288-5845 (from any location).

Pricing for International shipping destinations View USA Canada and Mexico Pricing

Cryopreserved

Cryopreserved Mice - Ready for Recovery

Price (US dollars $)
Cryorecovery* $2782.00
Animals Provided

At least two mice that carry the mutation (if it is a mutant strain) will be provided. Their genotypes may not reflect those discussed in the strain description. Please inquire for possible genotypes and see additional details below.

Standard Supply

Cryopreserved. Ready for recovery. Please refer to pricing and supply notes on the strain data sheet for further information.

Supply Notes

  • Cryorecovery - Standard.
    Progeny testing is not required.

    The average number of mice provided from recovery of our cryopreserved strains is 10. The total number of animals provided, their gender and genotype will vary. We will fulfill your order by providing at least two pair of mice, at least one animal of each pair carrying the mutation of interest. Please inquire if larger numbers of animals with specific genotype and genders are needed. Animals typically ship between 10 and 14 weeks from the date of your order. If a second cryorecovery is needed in order to provide the minimum number of animals, animals will ship within 25 weeks. IMPORTANT NOTE: The genotypes of animals provided may not reflect the mating scheme utilized by The Jackson Laboratory prior to cryopreservation, or that discussed in the strain description. Please inquire about possible genotypes which will be recovered for this specific strain. The Jackson Laboratory 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. For more information on Dedicated Supply, please contact JAX® Services, Tel: 1-800-422-6423 (from U.S.A., Canada or Puerto Rico only) or 1-207-288-5845 (from any location).

View USA Canada and Mexico Pricing View International Pricing

Standard Supply

Cryopreserved. Ready for recovery. Please refer to pricing and supply notes on the strain data sheet for further information.

Control Information

  Control
   005304 C57BL/6NJ (approximate)
 
  Considerations for Choosing Controls
  Control Pricing Information for Genetically Engineered Mutant Strains.
 

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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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