Overview

Also Known As:cyp27^-

Cyp27a1^tm1Elt mice (or sterol 27-hydroxylase-deficient mice) harbor a knock-out mutation of the cytochrome P450, family 27, subfamily a, polypeptide 1 locus that abolishes endogenous gene expression. These mice may be useful in studying the conversion of cholesterol to bile acids, as well as lipid and cholesterol homeostasis research.

Donating Investigator

Eran Leitersdorf, Hadassah University Hospital

Genetic overview

Genetic Background	Generation

Cyp27a1^tm1Elt

Allele Type	Gene Symbol	Gene Name
Targeted (Null/Knockout)	Cyp27a1	cytochrome P450, family 27, subfamily a, polypeptide 1

View Genetics

Research Applications

Metabolism Research
Research Tools
Internal/Organ Research
Endocrine Deficiency Research
Cardiovascular Research

View All Research Applications

Base Price

Starting at:

$2,854.50 Domestic price Cryo Recovery

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Details

Detailed Description

These mice harbor a targeted mutation of the Cyp27a1 (cytochrome P450, family 27, subfamily a, polypeptide 1) locus that abolishes endogenous
gene expression. Homozygous mice (also called Cyp27a1^-/-, cyp27^-/-, or sterol 27-hydroxylase-deficient mice) are viable and fertile, with no RNA or protein expression from the targeted gene detected in liver tissue. Both formation of bile acids and excretion of fecal bile acids are decreased in homozygous mice. Compensatory up-regulation of hepatic enzymes that convert cholesterol to bile acids (bile acid synthesis) is also observed. Cyp27a1^-/- mice exhibit a dramatic increase in cytochrome P450 3A (Cyp3a11) which catalyzes side-chain hydroxylations of bile acid intermediates subsequently facilitating their excretion in the bile and urine. Homozygous mice also have increased expression of other nuclear xenobiotic receptor PXR (pregnane X receptor) target genes.

Development

A targeting vector was designed to replace a 71 bp fragment of the Cyp27a1 (cytochrome P450, family 27, subfamily a, polypeptide 1) locus in exon 8 (upstream to the putative heme-binding site that is crucial for the activity of P-450 enzymes) with a neomycin resistance gene cassette. This construct was electroporated into 129Sv-derived embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts and chimeric mice were bred with C57BL/6J mice to generate the mutant colony. The donating investigator reported that the cyp27-mutant colony was subsequently backcrossed to C57BL/6J inbred mice (see SNP note below) for approximately 12 generations prior to sending to The Jackson Laboratory Repository. Upon arrival, mice were bred to C57BL/6J inbred mice (Stock No. 000664) for at least one generation to establish the colony.

A 32 SNP (single nucleotide polymorphism) panel analysis, with 27 markers covering all 19 chromosomes and the X chromosome, as well as 5 markers that distinguish between the C57BL/6J and C57BL/6N substrains, was performed on the rederived living colony at The Jackson Laboratory Repository. While the 27 markers throughout the genome suggested a C57BL/6 genetic background, 2 of 5 markers that determine C57BL/6J from C57BL/6N were found to be segregating. These data suggest the mice sent to The Jackson Laboratory Repository were on a mixed C57BL/6J ; C57BL/6N genetic background.

Control Suggestions

000664 C57BL/6J

Additional Information

Considerations for Choosing Controls

Selected References

Rosen H; Reshef A; Maeda N; Lippoldt A; Shpizen S; Triger L; Eggertsen G; Bjorkhem I; Leitersdorf E. 1998. Markedly reduced bile acid synthesis but maintained levels of cholesterol and vitamin D metabolites in mice with disrupted sterol 27-hydroxylase gene. J Biol Chem 273(24):14805-12PubMed: 9614081 MGI: J:48127

View All References

Genetics

Cyp27a1^tm1Elt

Allele Symbol: Cyp27a1^tm1Elt

Allele Name	targeted mutation 1, Eran Leitersdorf
Allele Type	Targeted (Null/Knockout)
Allele Synonym(s)	Cyp27 -; cyp27^-; Cyp27a1^-
Gene Symbol and Name	Cyp27a1, cytochrome P450, family 27, subfamily a, polypeptide 1
Gene Synonym(s)
Strain of Origin	129/Sv
Chromosome	1
Molecular Note	A 71 bp fragment of exon 8 was deleted and replaced with a neomycin resistance gene via homologous recombination. The mutant allele was verified by Northern blot analysis of liver extracts from homozygous mutant mice. Western blot analysis of total liver mitochondrial protein from homozygous mutants confirmed the absence of protein product.
Mutations Made By	Eran Leitersdorf, Hadassah University Hospital

Disease/Phenotype

Disease Terms

Research Areas By Phenotype

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

Metabolism Research
- Enzyme Deficiency
- Lipid Metabolism
Research Tools
- Metabolism Research
- Cardiovascular Research
Internal/Organ Research
- Liver Defects
- Gastrointestinal Defects
Endocrine Deficiency Research
- Gastrointestinal Defects
Cardiovascular Research
- Hypercholesterolemia
- Other
  - altered fat metabolism

Mammalian Phenotype Terms by Genotype

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

Genotype: Cyp27a1^tm1Elt/Cyp27a1^tm1Elt
involves: 129/Sv * C57BL/6J

digestive/alimentary phenotype

abnormal feces composition
- 2.5-fold increase in fecal neutral sterol excretion relative to wild-type controls
- fecal bile acid excretion is about 47% of that in wild-type controls

decreased intestinal cholesterol absorption
- intestinal cholesterol absorption is restored to normal levels by cholic acid feeding
- severe reduction in intestinal cholesterol absorption (4% from 54% in wild-type controls)

homeostasis/metabolism phenotype

abnormal bile salt homeostasis
- 5-fold increase in cholesterol 7alpha-hydroxylase activity relative to wild-type controls

abnormal circulating cholesterol level
- concentration of circulating 7-alpha hydroxycholesterol is 4-10 fold higher in null mice

abnormal vitamin D level
- levels of 25-hydroxyvitamin D are slightly higher in nulls than in wild-type

decreased bile salt level
- bile acid pool size is only 27% of that in wild-type controls
- total bile acid synthesis is about 47% of that in wild-type controls, as measured by the rate of fecal bile acid excretion

decreased cholesterol level
- slight reduction of cholesterol concentration in the lungs

decreased intestinal cholesterol absorption
- intestinal cholesterol absorption is restored to normal levels by cholic acid feeding
- severe reduction in intestinal cholesterol absorption (4% from 54% in wild-type controls)

increased cholesterol level
- 2.5-fold increase in whole animal cholesterol synthesis relative to wild-type controls, with ~90% attributed to hepatic synthesis
- 48% increase of cholesterol concentration in the adrenal glands relative to wild-type controls
- amount of 7 alpha-hydroxycholesterol in liver, kidney and brain is markedly higher in null animals
- cholic acid feeding reduces sterol synthesis in the liver and adrenal gland to values significantly below those seen in wild-type mice fed the basal diet alone
- marked increase in cholesterol synthesis in the liver and adrenal gland (4-fold), lung (2.9-fold), spleen (2.4-fold), and small intestine (1.8-fold)

increased circulating cholesterol level
- 30% increase in plasma total cholesterols level on a conventional low fat, low cholesterol diet

increased circulating triglyceride level
- 2-fold increase in plasma total triacylglycerol levels on a conventional low fat, low cholesterol diet
- plasma triacylglycerol levels are essentially normalized by cholic acid feeding

increased circulating VLDL cholesterol level
- marked increase in plasma cholesterol levels is confined to the VLDL fraction

increased circulating VLDL triglyceride level
- marked increase in plasma triacylglycerol levels is confined to the VLDL fraction

increased fatty acid level
- 70% increase in hepatic fatty acid synthesis relative to wild-type controls
- hepatic fatty acid synthesis is essentially normalized by cholic acid feeding
- marked shift in hepatic fatty acid composition with a ~70% increase in the proportion of oleic (18:1) to stearic acid (18:0)
- Normal - no change in the rates of fatty acid synthesis in adrenal gland, lung, or small intestine tissue

increased liver triglyceride level
- 2.4-fold increase in hepatic triacylglycerol levels relative to wild-type controls
- hepatic triacylglycerol levels are essentially normalized by cholic acid feeding

increased sterol level
- significant increase of two non-cholesterol sterols, identified as the two forms of lathosterol, in the adrenal glands, not detected in wild-type adrenals
- trace amounts of the two lathosterol forms (~4% of total tissue sterol content) in the lungs, unlike in wild-type controls

liver/biliary system phenotype

abnormal bile composition
- bile acid concentration in gallbladder bile is only 37% of that in wild-type controls
- concentration of bile acids in hydrolyzed bile sample from knockout mice is 0.9 mg/ml compared to about 8 mg/ml in a wild-type sample
- Normal - however, bile acid species are similar to those in wild-type controls, with cholic acid predominating in both cases
- molar ratio of cholesterol in gallbladder bile is double that in wild-type controls, due to a significant reduction in bile acid and phospholipid levels while biliary cholesterol concentration remains normal

enlarged liver
- hepatomegaly is almost fully reversed by cholic acid or chenodeoxycholic acid feeding
- significant hepatomegaly at 3-4 months of age

increased liver triglyceride level
- 2.4-fold increase in hepatic triacylglycerol levels relative to wild-type controls
- hepatic triacylglycerol levels are essentially normalized by cholic acid feeding

increased liver weight
- 40% increase in liver weight relative to wild-type controls

mammalian phenotype

homeostasis/metabolism phenotype
- Normal - males show normal plasma levels of glucose, corticosterone, ACTH, and testosterone at 3-4 months of age

nervous system phenotype

decreased brain weight
- significant reduction in brain weight at 3-4 months of age

renal/urinary system phenotype

decreased kidney weight
- significant reduction in kidney weight at 3-4 months of age

endocrine/exocrine gland phenotype

enlarged adrenal glands
- adrenomegaly is NOT reversed by cholic acid feeding
- significantly enlarged adrenal glands at 3-4 months of age

enlarged adrenocortical cells
- upon histology, adrenomegaly reflects cortical cell hypertrophy

increased adrenal gland weight
- 45% increase in adrenal gland weight relative to wild-type controls

growth/size/body region phenotype

enlarged liver
- hepatomegaly is almost fully reversed by cholic acid or chenodeoxycholic acid feeding
- significant hepatomegaly at 3-4 months of age

increased liver weight
- 40% increase in liver weight relative to wild-type controls

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

Genotype: Cyp27a1^tm1Elt/Cyp27a1^tm1Elt
B6.129-Cyp27a1/J

growth/size/body region phenotype

enlarged liver
- livers are enlarged by ~45%

homeostasis/metabolism phenotype

abnormal vitamin D level
- at 10 weeks of age, HPLC analysis revealed that serum 25(OH)D3 values are 52.2 ng/mL versus 19.4 ng/mL in wild-type controls
- Normal - in contrast, serum 1,25(OH)2D3 level is comparable to that in wild-type controls (51-68 pg/mL) at 5-16 weeks of age
- mice show a 2- to 3-fold increase in serum 25(OH)D3 level at 6-14 weeks of age, as determined by RIA analysis

decreased circulating phosphate level
- serum phosphorus level is decreased slightly from 12.3 mg/dL at 3-5 weeks of age to 10.2 mg/dL on maturity and remains stable thereafter

liver/biliary system phenotype

enlarged liver
- livers are enlarged by ~45%

References

Rosen H; Reshef A; Maeda N; Lippoldt A; Shpizen S; Triger L; Eggertsen G; Bjorkhem I; Leitersdorf E. 1998. Markedly reduced bile acid synthesis but maintained levels of cholesterol and vitamin D metabolites in mice with disrupted sterol 27-hydroxylase gene. J Biol Chem 273(24):14805-12PubMed: 9614081 MGI: J:48127

Additional - Cyp27a1^tm1Elt related

Technical Support

CONTACT TECHNICAL SUPPORT

Genotyping Protocols
- End Point Analysis:Crb1End Point
- Standard PCR:Cyp27a1
- Genotyping resources and troubleshooting
Breeding Considerations

When maintaining a live colony, the donating investigator breeds heterozygous mice with wildtype siblings or C57BL/6J inbred mice (see Stock No. 000664). Homozygous mice may bred bred together.
- Additional Breeding and Husbandry Support
Mating System
- inbred x homozygous
  heterozygous x heterozygous
  heterozygous x homozygous
  homozygous x heterozygous,
  homozygous x homozygou
- Homozygote x Homozygote
Citation
When using the cyp27^- mouse strain in a publication, please cite the originating article(s) and include JAX stock #009106 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 Cyp27a1<tm1Elt>

Related Products and Services

Frozen Mouse Embryo	B6.129-Cyp27a1<tm1Elt>/J	$2595.00
Frozen Mouse Embryo	B6.129-Cyp27a1<tm1Elt>/J	$2595.00
Frozen Mouse Embryo	B6.129-Cyp27a1<tm1Elt>/J	$3373.50
Frozen Mouse Embryo	B6.129-Cyp27a1<tm1Elt>/J	$3373.50

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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. 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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Also Known As:cyp27-

Donating Investigator

Genetic overview

Research Applications

Base Price

Detailed Description

Development

Control Suggestions

Additional Information

Selected References

Cyp27a1tm1Elt

Allele Symbol: Cyp27a1tm1Elt

Disease Terms

Research Areas By Phenotype

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

Mammalian Phenotype Terms by Genotype

Genotype: Cyp27a1tm1Elt/Cyp27a1tm1Eltinvolves: 129/Sv * C57BL/6J

digestive/alimentary phenotype

homeostasis/metabolism phenotype

liver/biliary system phenotype

mammalian phenotype

nervous system phenotype

renal/urinary system phenotype

endocrine/exocrine gland phenotype

growth/size/body region phenotype

Genotype: Cyp27a1tm1Elt/Cyp27a1tm1EltB6.129-Cyp27a1/J

growth/size/body region phenotype

homeostasis/metabolism phenotype

liver/biliary system phenotype

References

Additional - Cyp27a1tm1Elt related

Genotyping Protocols

Breeding Considerations

Mating System

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

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:cyp27^-

Cyp27a1^tm1Elt

Allele Symbol: Cyp27a1^tm1Elt

Genotype: Cyp27a1^tm1Elt/Cyp27a1^tm1Elt
involves: 129/Sv * C57BL/6J

Genotype: Cyp27a1^tm1Elt/Cyp27a1^tm1Elt
B6.129-Cyp27a1/J

Additional - Cyp27a1^tm1Elt related