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 Mutant Stock; Targeted Mutation; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Species laboratory mouse Generation N1   Donating Investigator David Russell,   Univ of Texas Southwest Med Ctr Dallas

Appearance
black
Related Genotype: a/a

Description
Heterozygous carriers of the disrupted Cyp7a1 gene are phenotypically normal, viable, and fertile. Homozygous animals appear normal at birth but most die within the first 18 days of life. The 10-15% of homozygotes that survive are fertile. Newborn animals with a homozygous mutation in the Cyp7a1 gene lack bile acids, causing fat malabsorption as manifest by severe steatorrhea (fatty stools), deficiency of fat-soluble vitamins, and wasting due to malnutrition. Approximately 40% of the homozygotes die between postnatal days 1-4; 45% between days 11-18. Vitamin supplements given to nursing mothers can prevent deaths during the early period; cholic acid supplements in the mother's diet can prevent deaths in the later period. Mutant pups born to homozygous mothers not maintained on dietary supplements are noticeably smaller than age-matched heterozygous and wild type siblings. The skin of nursing homozygotes can be dry and scaly in appearance. Nursing heterozygous and homozygous mothers and their mutant pups not treated with cholic acid develop an unusually oily coat. No immunoreactive or enzymatically active Cyp7a1 proteins are produced in homozygous mutants, but a novel "hybrid" mRNA present in heterozygous and homozygous animals is composed of sequences derived from the 5' and 3' ends of the mutated gene.

Development
Disruption of the murine Cyp7a1 gene was carried out in AB-1 embryonic stem cells (derived from the 129S5/SvEvBrd strain) which were injected into C57BL/6J blastocysts. A neomycin cassette replaces most of exon 3, and all of exons 4 and 5 of the gene.

Control Information

	Control
	101045 B6129SF2/J	(approximate)
Considerations for Choosing Controls

Phenotype

Phenotype Information

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

Cyp7a1^tm1Rus/Cyp7a1^tm1Rus

        involves: 129S7/SvEvBrd * C57BL/6J

• lethality-prenatal/perinatal
• perinatal lethality (MGI Ref ID J:34342)
  • homozygotes born in expected numbers
  • high rate of mortality when mothers fed a normal diet
• lethality-postnatal
• postnatal lethality (MGI Ref ID J:34342)
  • without dietary supplementation, 85% die within the first 18 days postnatally
  • perinatal lethality extends through day 4 and results in 40% mortality
  • further mortality occurs after age 11 days and results in a total postnatal lethality of 85%
  • supplementation with vitamins and cholic acid begun at E12 results in normal survival
• growth/size phenotype
• abnormal prenatal growth/weight/body size (MGI Ref ID J:34342)
  • pups noticably smaller than normal when maternal diet has not been supplemented
• postnatal growth retardation (MGI Ref ID J:34342)
  • slow growth to 5 days then very little growth to day 11 when maternal diet is not supplemented
• homeostasis/metabolism phenotype
• abnormal bile salt homeostasis (MGI Ref ID J:34342)
  • cholic acid supplementation of maternal diet has no affect on early deaths but prevents later ones
• abnormal bile salt level (MGI Ref ID J:34870)
  • reduced levels of bile acids in stools
• abnormal fat-soluble vitamin level (MGI Ref ID J:34342)
  • supplementation with vitamins and cholic acid begun at E12 results in normal survival
  • vitamins in water reduces early wave of deaths but has no affect on later deaths
  • supplementation begun at birth still results in 60% mortality before age 14 days
  • reduced tissue levels of vitamins D3 and E, improved to varying degrees by vitamin and cholic acid supplementation
• abnormal lipid homeostasis (MGI Ref ID J:34870)
  • secretion of a mixture of monoglyeride esters causes oil coat of nursing females and oily skin of nursing pups
• decreased cholesterol absorption (MGI Ref ID J:114411)
  • nearly absent
• digestive/alimentary phenotype
• decreased cholesterol absorption (MGI Ref ID J:114411)
  • nearly absent
• steatorrhea (MGI Ref ID J:34342)
  • pups produce fatty stools
• skin/coat/nails phenotype
• abnormal skin condition/ morphology (MGI Ref ID J:34342)
• abnormal skin condition (MGI Ref ID J:34342)
• dry skin (MGI Ref ID J:34342)
  • on 5 day pups
• flaky skin (MGI Ref ID J:34342)
  • on 5 day pups
• oily skin (MGI Ref ID J:34342)
  • nursing pups develop an oily skin and usually die
  • skin becomes "normal" after 7 days
• abnormal skin morphology (MGI Ref ID J:34342)
• abnormal epidermis stratum basale morphology (MGI Ref ID J:34342)
  • compressed
• abnormal epidermis stratum granulosum morphology (MGI Ref ID J:34342)
  • thickened
• hyperkeratosis (MGI Ref ID J:34342)
  • cornified layer of the epidermis is thickened
• thin dermal layer (MGI Ref ID J:34342)
  • compressed
• thin epidermis stratum spinosum (MGI Ref ID J:34342)
  • compressed
• greasy coat (MGI Ref ID J:34342)
  • nursing homozygous (and heterozygous) mothers develop a very oily coat which lasts for a minimum of 7 and up to 14 days
• vision/eye phenotype
• abnormal vision (MGI Ref ID J:34342)
  • reduced exploratory behavior after openning of eyelids suggestive of reduced vision
• delayed eyelid opening (MGI Ref ID J:34342)
  • eyelid openning 8-9 days later than normal
  • excessive secretions from between the lids
• behavior/neurological phenotype
• decreased exploration in new environment (MGI Ref ID J:34342)
• hypoactivity (MGI Ref ID J:34342)
  • reduced exploratory behavior after opening of eyelids suggestive of reduced vision
• liver/biliary system phenotype
• abnormal bile composition (MGI Ref ID J:34870)
  • reduced cholic acid in bile relative to controls while some other bile acids are elevated
• abnormal liver morphology (MGI Ref ID J:34342)
  • yellow crystalline deposits in the liver
• abnormal liver physiology (MGI Ref ID J:34342)
  • increased conjugated bilirubin

Genes & Alleles

Gene & Allele Information

Allele Symbol		Cyp7a1tm1Rus
Allele Name		targeted mutation 1, David W Russell
Allele Type		Targeted (knock-out)
Common Name(s)		CYP7A1-; Cyp7-;
Mutation Made By		David Russell,   Univ of Texas Southwest Med Ctr Dallas
Strain of Origin		129S7/SvEvBrd-Hprt1<+>
ES Cell Line Name		AB1
ES Cell Line Strain		129S7/SvEvBrd-Hprt1<+>
Gene Symbol and Name		Cyp7a1, cytochrome P450, family 7, subfamily a, polypeptide 1
Chromosome		4
Gene Common Name(s)		CHAP; CP7A; CYP7; CYP7S1; MGC126826; MGC138389; cholesterol 7 alpha hydroxylase;
Molecular Note		A genomic fragment containing part of exon 3, exon 4 and exon 5 was replaced with a neomycin selection cassette. Activity assays on extracts of liver microsomal memebrane preparations derived from homozygous mice demonstrated that no functional protein is made from this allele. [MGI Ref ID J:34342]

Genotyping

Genotyping Information

Genotyping Protocols

Cyp7a1^tm1Rus, SEP PCR, vers. 2

Helpful Links

Genotyping resources and troubleshooting

References

References

Selected Reference(s)

Ishibashi S; Schwarz M; Frykman PK; Herz J; Russell DW. 1996. Disruption of cholesterol 7alpha-hydroxylase gene in mice. I. Postnatal lethality reversed by bile acid and vitamin supplementation. J Biol Chem 271(30):18017-23. [PubMed: 8663429]  [MGI Ref ID J:34342]

Additional References

Chen JY; Levy-Wilson B; Goodart S; Cooper AD. 2002. Mice expressing the human CYP7A1 gene in the mouse CYP7A1 knock-out background lack induction of CYP7A1 expression by cholesterol feeding and have increased hypercholesterolemia when fed a high fat diet. J Biol Chem 277(45):42588-95. [PubMed: 12202481]  [MGI Ref ID J:80051]

Erickson SK; Lear SR; Deane S; Dubrac S; Huling SL; Nguyen L; Bollineni JS; Shefer S; Hyogo H; Cohen DE; Shneider B; Sehayek E; Ananthanarayanan M; Balasubramaniyan N; Suchy FJ; Batta AK; Salen G. 2003. Hypercholesterolemia and changes in lipid and bile acid metabolism in male and female cyp7A1-deficient mice. J Lipid Res 44(5):1001-9. [PubMed: 12588950]  [MGI Ref ID J:83458]

Faust PL. 2003. Abnormal cerebellar histogenesis in PEX2 Zellweger mice reflects multiple neuronal defects induced by peroxisome deficiency. J Comp Neurol 461(3):394-413. [PubMed: 12746876]  [MGI Ref ID J:83644]

Schwarz M; Lund EG; Setchell KDR; Kayden HJ; Zerwekh JE; Bjorkhem I; Herz J; Russell DW. 1996. Disruption of cholesterol 7alpha-hydroxylase gene in mice. II. Bile acid deficiency is overcome by induction of oxysterol 7alpha-hydroxylase. J Biol Chem 271(30):18024-31. [PubMed: 8663430]  [MGI Ref ID J:34870]

Schwarz M; Russell DW; Dietschy JM; Turley SD. 2001. Alternate pathways of bile acid synthesis in the cholesterol 7alpha-hydroxylase knockout mouse are not upregulated by either cholesterol or cholestyramine feeding. J Lipid Res 42(10):1594-603. [PubMed: 11590215]  [MGI Ref ID J:72319]

Cyp7a1^tm1Rus related

Agellon LB; Drover VA; Cheema SK; Gbaguidi GF; Walsh A. 2002. Dietary cholesterol fails to stimulate the human cholesterol 7alpha-hydroxylase gene (CYP7A1) in transgenic mice. J Biol Chem 277(23):20131-4. [PubMed: 11967256]  [MGI Ref ID J:77084]

Arnon R; Yoshimura T; Reiss A; Budai K; Lefkowitch JH; Javitt NB. 1998. Cholesterol 7-hydroxylase knockout mouse: a model for monohydroxy bile acid-related neonatal cholestasis. Gastroenterology 115(5):1223-8. [PubMed: 9797378]  [MGI Ref ID J:51019]

Chen JY; Levy-Wilson B; Goodart S; Cooper AD. 2002. Mice expressing the human CYP7A1 gene in the mouse CYP7A1 knock-out background lack induction of CYP7A1 expression by cholesterol feeding and have increased hypercholesterolemia when fed a high fat diet. J Biol Chem 277(45):42588-95. [PubMed: 12202481]  [MGI Ref ID J:80051]

Erickson SK; Lear SR; Deane S; Dubrac S; Huling SL; Nguyen L; Bollineni JS; Shefer S; Hyogo H; Cohen DE; Shneider B; Sehayek E; Ananthanarayanan M; Balasubramaniyan N; Suchy FJ; Batta AK; Salen G. 2003. Hypercholesterolemia and changes in lipid and bile acid metabolism in male and female cyp7A1-deficient mice. J Lipid Res 44(5):1001-9. [PubMed: 12588950]  [MGI Ref ID J:83458]

Faust PL. 2003. Abnormal cerebellar histogenesis in PEX2 Zellweger mice reflects multiple neuronal defects induced by peroxisome deficiency. J Comp Neurol 461(3):394-413. [PubMed: 12746876]  [MGI Ref ID J:83644]

Post SM; Groenendijk M; Solaas K; Rensen PC; Princen HM. 2004. Cholesterol 7alpha-hydroxylase deficiency in mice on an APOE*3-Leiden background impairs very-low-density lipoprotein production. Arterioscler Thromb Vasc Biol 24(4):768-74. [PubMed: 14962946]  [MGI Ref ID J:102144]

Post SM; Groenendijk M; van der Hoogt CC; Fievet C; Luc G; Hoekstra M; Princen HM; Staels B; Rensen PC. 2006. Cholesterol 7alpha-hydroxylase deficiency in mice on an APOE*3-Leiden background increases hepatic ABCA1 mRNA expression and HDL-cholesterol. Arterioscler Thromb Vasc Biol 26(12):2724-30. [PubMed: 17008588]  [MGI Ref ID J:128088]

Schwarz M; Lund EG; Setchell KDR; Kayden HJ; Zerwekh JE; Bjorkhem I; Herz J; Russell DW. 1996. Disruption of cholesterol 7alpha-hydroxylase gene in mice. II. Bile acid deficiency is overcome by induction of oxysterol 7alpha-hydroxylase. J Biol Chem 271(30):18024-31. [PubMed: 8663430]  [MGI Ref ID J:34870]

Schwarz M; Russell DW; Dietschy JM; Turley SD. 2001. Alternate pathways of bile acid synthesis in the cholesterol 7alpha-hydroxylase knockout mouse are not upregulated by either cholesterol or cholestyramine feeding. J Lipid Res 42(10):1594-603. [PubMed: 11590215]  [MGI Ref ID J:72319]

Schwarz M; Russell DW; Dietschy JM; Turley SD. 1998. Marked reduction in bile acid synthesis in cholesterol 7alpha-hydroxylase-deficient mice does not lead to diminished tissue cholesterol turnover or to hypercholesterolemia. J Lipid Res 39(9):1833-43. [PubMed: 9741696]  [MGI Ref ID J:120425]

Tiemann M; Han Z; Soccio R; Bollineni J; Shefer S; Sehayek E; Breslow JL. 2004. Cholesterol feeding of mice expressing cholesterol 7alpha-hydroxylase increases bile acid pool size despite decreased enzyme activity. Proc Natl Acad Sci U S A 101(7):1846-51. [PubMed: 14762172]  [MGI Ref ID J:88391]

Voshol PJ; Schwarz M; Rigotti A; Krieger M; Groen AK; Kuipers F. 2001. Down-regulation of intestinal scavenger receptor class B, type I (SR-BI) expression in rodents under conditions of deficient bile delivery to the intestine. Biochem J 356(Pt 2):317-25. [PubMed: 11368757]  [MGI Ref ID J:114411]

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

Colony Maintenance

Breeding & Husbandry	This strain requires a cholic acid dietary supplement. Cholic acid is mixed and fed with milled food at the concentration 1g cholic acid/100g milled food. A vitamin supplement may also be required. Mice from the B6129F2/J colony (Stock 101045) may be used as controls. The B6129F2/J mice only provide an approximate match to this B6,129 background. Expected coat color from breeding:Black
Diet Information	LabDiet® 5K52/5K67

Purchasing information

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

Pricing

Supply Details

Standard Supply

Cryopreserved. Ready for recovery. Please refer to pricing and supply notes for further information.

Supply Notes

Cryorecovery - Standard. At least two animals carrying the mutation of interest will be provided. The total number of animals provided, their gender and genotype will vary. Please inquire if larger numbers of animals with specific genotype and genders are needed. Animals typically ship between 13 and 16 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). 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
	101045 B6129SF2/J	(approximate)
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.

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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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