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

Former Names C.129S4-Ncb5ortm1Hfb/HfbJ    (Changed: 29-SEP-05 ) Type Congenic; Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Additional information on Congenic nomenclature. Species laboratory mouse Background Strain BALB/cAnN Donor Strain 129S4 Generation N11p Generation Definitions   Donating Investigator H. Bunn,   Brigham and Womens Hospital

Appearance
pink-eye, albino
Related Genotype: A/? Tyr^c/Tyr^c

Description
Mice heterozygous for the targeted mutation are viable and fertile, glucose tolerant, have normal blood sugar levels, serum lipid profiles and white adipose tissue mass.

No protein from the targeted gene was detected by Western Blot analysis of mice homozygous for the allele. Homozygous mice consume more food, have decreased adipose tissue mass and are hyperlipidemic compared to wildtype controls post-weaning. At 4 weeks of age glucose levels are normal but insulin levels are 40% of wildtype controls. At 7 weeks of age clinical diabetes is present in both male and female of homozygous mice. Histological evaluation of pancreas from 21 week old homozygote animals revealed a significant reduction in the number of islets and decreased cytoplasmic to nuclear ratio in the islet cells and there was no insulitis nor phagocytosis of necrotic beta cell fragments. While there is a progressive loss of beta cells in aging homozygous mice, there is no loss of alpha, delta or PP cells. Electron microscopy reveals degranulated beta cells and hypertrophic and hyperplastic mitochodria.

This strain is useful in islet transplantation research, stem cell research and as a tool for studying the role of oxidative stress in diabetes.

Development
A construct containing a hygromycin expression cassette replaces a region extending from the 3' end of exon 3 to the 5' end of intron 4 of Cyb5r4 (cloned from a 129/Sv mouse), deleting exon 4 the heme binding domain crucial to enzyme stability and biochemical properties, was transfected into 129S4/SvJae embryonic stem cells (ES cells). These ES cells were injected into BALB/cAnN blastocysts. Chimeric founders were mated to BALB/cAnN and subsequently intercrossed to generate homozygotes. In 2005, the Type 1 Diabetes Resource received heterozygous C.129S4-Cyb5r4^tm1Hfb/HfbJ at generation N10; mated to BALB/cJ once prior to mating wildtype sibling x heterozygous.

Control Information

	Control
	Wild-type female from the colony
Considerations for Choosing Controls

Related Strains

Strains carrying   Cyb5r4^tm1Hfb allele

005517

B6.129S4-Cyb5r4tm1Hfb/HfbJ

View Strains carrying   Cyb5r4^tm1Hfb     (1 strain)

Strains carrying other alleles of Cyb5r4

005517

B6.129S4-Cyb5r4tm1Hfb/HfbJ

View Strains carrying other alleles of Cyb5r4     (1 strain)

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI

Diabetes Mellitus, Noninsulin-Dependent; NIDDM - Models with phenotypic similarity to human disease where etiologies are distinct.2

2 Human genes are associated with this disease. Orthologs of those genes do not appear in the mouse genotype(s).

View Mammalian Phenotype Terms

Mammalian Phenotype Terms provided by MGI

      assigned by genotype

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

Cyb5r4^tm1Hfb/Cyb5r4^tm1Hfb

        involves: 129S4/SvJae * BALB/cAnN

• homeostasis/metabolism phenotype
• abnormal glucose homeostasis   (MGI Ref ID J:91486)
• • decreased circulating insulin level
    • insulin levels 40% of normal at 4 weeks of age   (MGI Ref ID J:91486)
    • insulin levels 25% normal at 7 weeks of age and barely detectable after fasting   (MGI Ref ID J:91486)
  • decreased insulin secretion
    • early defect in glucose stimulated insulin secretion but not in glucose sensing pathway   (MGI Ref ID J:91486)
  • impaired glucose tolerance
    • impaired tolerance for glucose given ip at 4 weeks of age   (MGI Ref ID J:91486)
  • increased circulating glucose level
    • normal glucose levels at 4 weeks of age in a fed state   (MGI Ref ID J:91486)
    • by 7 weeks of age blood glucose is 3X normal in the fed state or after overnight fasting   (MGI Ref ID J:91486)
  • increased insulin sensitivity
    • insulin tolerance is normal but with a slight increase in insulin sensitivity   (MGI Ref ID J:91486)
• hyperlipidemia   (MGI Ref ID J:91486)
• endocrine/exocrine gland phenotype
• abnormal pancreatic islet morphology
  • decreased cytoplasm to nuclear ratio in islet cells   (MGI Ref ID J:91486)
  • no inflammatory cells or necrotic beta cells   (MGI Ref ID J:91486)
  • cell distribution pattern normal at 4 weeks of age   (MGI Ref ID J:91486)
• • decreased pancreatic beta cell number
    • beta cell numbers decreased at 7 weeks of age   (MGI Ref ID J:91486)
    • at 21 weeks a very small number of beta cells are left   (MGI Ref ID J:91486)
    • increased size and number of mitochondria   (MGI Ref ID J:91486)
• decreased insulin secretion
  • early defect in glucose stimulated insulin secretion but not in glucose sensing pathway   (MGI Ref ID J:91486)
• adipose tissue phenotype
• decreased total body fat amount
  • decreased adipose tissue mass   (MGI Ref ID J:91486)
• behavior/neurological phenotype
• abnormal eating behavior
  • increased food intake   (MGI Ref ID J:91486)

View Research Applications

Research Applications

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

Diabetes and Obesity Research
Hyperglycemia
Hypoinsulinemia
Impaired Insulin Processing
Insulin Receptors and Growth Factors
Islet Transplantation Studies
Type 1 Diabetes (IDDM)
      MODY, mature onset diabetes of the young

Endocrine Deficiency Research
Pancreas Defects

Metabolism Research
Lipid Metabolism

Research Tools
Apoptosis Research

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Cyb5r4tm1Hfb
Allele Name		targeted mutation 1, H Franklin Bunn
Allele Type		Targeted (knock-out)
Common Name(s)		Ncb5or-;
Mutation Made By		H. Bunn,   Brigham and Womens Hospital
Strain of Origin		129S4/SvJae
Gene Symbol and Name		Cyb5r4, cytochrome b5 reductase 4
Chromosome		9
Gene Common Name(s)		2810034J18Rik; B5+B5R; C79736; NADPH cytochrome B5 oxidoreductase; NCB5OR; Ncb5or; RIKEN cDNA 2810034J18 gene; RP4-676J13.1; b5&b5R; b5/b5r; cb5/cb5R; dJ676J13.1; expressed sequence C79736;
Molecular Note		Exon 4, which contains sequence encoding the heme-binding domain, was replaced with a PGK-hygromycin gene. Mutant mice did not express full length mRNA or protein, as shown by Northern blot and Western blot, respectively. [MGI Ref ID J:91486]

Genotyping

Genotyping Information

Genotyping Protocols

Cyb5r4^tm1Hfb, Separated PCR

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Xie J; Zhu H; Larade K; Ladoux A; Seguritan A; Chu M; Ito S; Bronson RT; Leiter EH; Zhang CY; Rosen ED; Bunn HF. 2004. Absence of a reductase, NCB5OR, causes insulin-deficient diabetes. Proc Natl Acad Sci U S A 101(29):10750-5. [PubMed: 15247412]  [MGI Ref ID J:91486]

Additional References

Cyb5r4^tm1Hfb related

Larade K; Jiang Z; Zhang Y; Wang W; Bonner-Weir S; Zhu H; Bunn HF. 2008. Loss of Ncb5or results in impaired fatty acid desaturation, lipoatrophy, and diabetes. J Biol Chem 283(43):29285-91. [PubMed: 18682384]  [MGI Ref ID J:142474]

Xu M; Wang W; Frontera JR; Neely MC; Lu J; Aires D; Hsu FF; Turk J; Swerdlow RH; Carlson SE; Zhu H. 2011. Ncb5or deficiency increases Fatty Acid catabolism and oxidative stress. J Biol Chem 286(13):11141-54. [PubMed: 21300801]  [MGI Ref ID J:170917]

Zhang Y; Larade K; Jiang ZG; Ito S; Wang W; Zhu H; Bunn HF. 2010. The flavoheme reductase Ncb5or protects cells against endoplasmic reticulum stress-induced lipotoxicity. J Lipid Res 51(1):53-62. [PubMed: 19609006]  [MGI Ref ID J:157053]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Production of mice from cryopreserved embryos or sperm occurs in a maximum barrier room, RG10/RG30.

Purchasing information

Pricing, Supply Level & Notes, Controls

General Supply Notes

• This strain is included in the Type 1 Diabetes Repository collection.

Control Information

	Control
	Wild-type female from the colony
Considerations for Choosing Controls
Control Pricing Information for Genetically Engineered Mutant Strains.

Payment Terms and Conditions

Terms are granted by individual review and stated on the customer invoice(s) and account statement. These transactions are payable in U.S. currency within the granted terms. Payment for services, products, shipping containers, and shipping costs that are rendered are expected within the payment terms indicated on the invoice or stated by contract. Invoices and account balances in arrears of stated terms may result in The Jackson Laboratory pursuing collection activities including but not limited to outside agencies and court filings.

See Terms of Use tab for General Terms and Conditions

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.

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