Description

Strain Information

Type Congenic; Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered Mutant Mice. Mating System +/+ sibling x Heterozygote         (Female x Male) Species laboratory mouse Generation N9+N1F1 (10-SEP-08)   Donating Investigator Shailesh Patel,   Medical College of Wisconsin

Description
Mice homozygous for the Dhcr7^Ex8 allele lack the exon 8 coding sequence and flanking splice acceptor site of the targeted gene, resulting in the truncated DHCR7 mutation most frequently observed in Smith-Lemli-Opitz/RSH Syndrome (SLOS) patients (IVS8-1G > C). Although a truncated product is transcribed from the targeted gene, no mRNA containing the deleted 3'-coding region is detected in homozygous liver or brain tissue. Homozygous mice exhibit the same biochemical defects as observed with SLOS patients, including markedly reduced tissue cholesterol and total sterol levels, and 30- to 40-fold elevated concentrations of 7-dehydrocholesterol. Newborn homozygotes have difficulty breathing, do not suckle, and die soon after birth with immature lungs, enlarged bladder, and, frequently, cleft palate. These Dhcr7^Ex8 mutant mice may be useful in studying Smith-Lemli-Opitz/RSH Syndrome (SLOS; a birth-defect mental-retardation syndrome) or other metabolic disorders involved with cholesterol biosynthesis.

Development
A targeting vector containing a neomycin resistance gene was used to disrupt exon 8. The construct was electroporated into 129P2/OlaHsd derived E14TG2a embryonic stem (ES) cells. Correctly targeted ES cells were injected into C57BL/6 blastocysts. The mice were then bred to mice carrying the Apoe^tm1Unc allele (on a C57BL/6J congenic background), and then backcrossed to C57BL/6 for 8 generations prior to arriving at The Jackson Laboratory. Upon arrival, mice were bred to C57BL/6J to remove the Apoe^tm1Unc allele. These mice carry only the Dhcr7^Ex8 mutant allele (also called Dhcr7^tm1Gst).

Control Information

	Control
	Wild-type from the colony
	000664 C57BL/6J
Considerations for Choosing Controls

Additional Web Information

Congenic Nomenclature

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms

Smith-Lemli-Opitz Syndrome; SLOS - Models with phenotypic similarity to human disease where etiologies involve orthologs.1

1 Human genes are associated with this disease. Orthologs of those genes appear in the mouse genotype(s).

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

Dhcr7^tm1Gst/Dhcr7^tm1Gst

        B6.129P2-Dhcr7^tm1Gst

• lethality-prenatal/perinatal
• neonatal lethality (MGI Ref ID J:93296)
  • die within 24 hours and most within 14 hours of birth
• growth/size phenotype
• decreased body size (MGI Ref ID J:93296)
  • at birth
• fetal growth retardation (MGI Ref ID J:93296)
  • growth retardation beginning at E14.5-E16.5
• respiratory system phenotype
• abnormal breathing (MGI Ref ID J:93296)
  • breathing is irregular and shallow
• apnea (MGI Ref ID J:93296)
  • breathing is irregular and shallow, with long periods of apnea
• decreased breathing frequency (MGI Ref ID J:93296)
  • breathing frequency is slower
• abnormal lung development (MGI Ref ID J:93296)
  • lungs show varying severity of impaired pre-alveolar development, including delayed saccular development from E17.5 onwards
  • lungs exhibit delayed differentiation of type I alveolar epithelial cells (AEC), however differentiation of type II AECs is normal
• abnormal lung morphology (MGI Ref ID J:93296)
• abnormal lung epithelium morphology (MGI Ref ID J:93296)
  • lungs exhibit delayed expansion of epithelial tubules
• abnormal type I pneumocyte morphology (MGI Ref ID J:93296)
  • lungs exhibit a delay in differentiation of type I alveolar epithelial cells (AEC) as indicated by fewer flattened type I cells annd reduced expression of type I AEC markers
• abnormal lung vasculature (MGI Ref ID J:93296)
  • marker analysis indicates a delay in lung vascular development, with an undeveloped pulmonary capillary bed at E20.5
• abnormal respiratory alveoli morphology (MGI Ref ID J:93296)
  • lungs exhibit less septation compared to controls
  • cell proliferation is reduced in distal lungs at E18.5 and E20.5
• abnormal type I pneumocyte morphology (MGI Ref ID J:93296)
  • lungs exhibit a delay in differentiation of type I alveolar epithelial cells (AEC) as indicated by fewer flattened type I cells annd reduced expression of type I AEC markers
• small lung (MGI Ref ID J:93296)
• decreased lung weight (MGI Ref ID J:93296)
• pulmonary hypoplasia (MGI Ref ID J:93296)
• behavior/neurological phenotype
• no spontaneous movement (MGI Ref ID J:93296)
  • lack of spontaneous movement in newborns
• cardiovascular system phenotype
• abnormal lung vasculature (MGI Ref ID J:93296)
  • marker analysis indicates a delay in lung vascular development, with an undeveloped pulmonary capillary bed at E20.5
• homeostasis/metabolism phenotype
• abnormal lipid level (MGI Ref ID J:93296)
  • total sterols at birth are reduced in lungs by about 30%
• decreased cholesterol level (MGI Ref ID J:93296)
  • cholesterol content in lungs remains at almost constant low levels between E13.5 and P0 instead of increasing as in controls
• hypoxia (MGI Ref ID J:93296)
• increased circulating corticosterone level (MGI Ref ID J:93296)
  • plasma corticosterone levels in P0 mutants is increased by about 40%

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

Dhcr7^tm1Gst/Dhcr7^tm1Gst

        involves: 129P2/OlaHsd

• lethality-prenatal/perinatal
• neonatal lethality (MGI Ref ID J:71611)
  • all die within 18 hours after birth, presumably from respiratory failure or dehydration
• growth/size phenotype
• decreased body weight (MGI Ref ID J:71611)
• respiratory system phenotype
• abnormal lung development (MGI Ref ID J:71611)
  • lungs of newborns are similar in appearance to normal 15- to 16-gestational day mice, suggesting that lungs may be immature
• abnormal lung morphology (MGI Ref ID J:71611)
  • compact lungs with sparse, unconnected air spaces
• respiratory failure (MGI Ref ID J:71611)
• behavior/neurological phenotype
• hypoactivity (MGI Ref ID J:71611)
  • lack movement shortly after birth
• no suckling reflex (MGI Ref ID J:71611)
  • none of the pups suckle
• homeostasis/metabolism phenotype
• abnormal cholesterol homeostasis (MGI Ref ID J:71611)
  • 30- to 40-fold elevation in 7-dehydrocholesterol (7DHC) levels in the brain and liver
  • 7-dehydrodesmosterol is accumulated in the brain whereas desmosterol is not detected
• decreased cholesterol level (MGI Ref ID J:71611)
  • decrease in cholesterol levels in the brain and liver
• abnormal enzyme/ coenzyme level (MGI Ref ID J:71611)
  • levels of HMG-CoA reductase protein are reduced
• abnormal enzyme/coenzyme activity (MGI Ref ID J:71611)
  • HMG-CoA reductase activities are reduced 6-fold in the liver and 2.7-fold in brain microsomes
• abnormal lipid level (MGI Ref ID J:71611)
  • decrease in total sterol levels in the brain and liver
• decreased cholesterol level (MGI Ref ID J:71611)
  • decrease in cholesterol levels in the brain and liver
• renal/urinary system phenotype
• distended urinary bladder (MGI Ref ID J:71611)
  • 90% exhibit greatly distended urinary bladder
• craniofacial phenotype
• cleft palate (MGI Ref ID J:71611)
  • 12% exhibit cleft palate
• digestive/alimentary phenotype
• cleft palate (MGI Ref ID J:71611)
  • 12% exhibit cleft palate

View Research Applications

Research Applications

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

Cardiovascular Research
Metabolic Syndrome
Other (altered fat metabolism)
Other (altered lipoprotein profile)

Developmental Biology Research
Perinatal Lethality (Homozygous)

Metabolism Research
Enzyme Deficiency
Lipid Metabolism

Research Tools
Metabolism Research

Genes & Alleles

Gene & Allele Information

Allele Symbol		Dhcr7tm1Gst
Allele Name		targeted mutation 1, G S Tint
Allele Type		Targeted (knock-out)
Common Name(s)		Dhcr7-; Dhr7delEx8;
Mutation Made By		Hongwei Wu,   Medical College of Wisconsin
Strain of Origin		129P2/OlaHsd
ES Cell Line Name		E14TG2a
ES Cell Line Strain		129P2/OlaHsd
Gene Symbol and Name		Dhcr7, 7-dehydrocholesterol reductase
Chromosome		7
Gene Common Name(s)		AA409147; MGC93039; SLOS; expressed sequence AA409147;
Molecular Note		A mutation commonly found in human Smith-Lemli-Opitz/RSH syndrome (SLOS) was mimicked in mouse by replacement of exon 8 and the flanking regions with a PGK-neo cassette in the reverse orientation. The mutation results in deletion of 1/3 of the protein from amino acids 318-471. RT-PCR analysis of liver mRNA from homozygous mutant animals did not amplify a product using primers to the 3' end of the gene. Western blot analysis using antibodies recognizing residues 454-467 of the human protein did not detectprotein product in liver proteins from homozygous mutants. [MGI Ref ID J:71611]

Genotyping

Genotyping Information

Genotyping Protocols

Dhcr7^tm1Gst, STD PCR, vers. 1

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

Fitzky BU; Moebius FF; Asaoka H; Waage-Baudet H; Xu L; Xu G; Maeda N; Kluckman K; Hiller S; Yu H; Batta AK; Shefer S; Chen T; Salen G; Sulik K; Simoni RD; Ness GC; Glossmann H; Patel SB; Tint GS. 2001. 7-Dehydrocholesterol-dependent proteolysis of HMG-CoA reductase suppresses sterol biosynthesis in a mouse model of Smith-Lemli-Opitz/RSH syndrome. J Clin Invest 108(6):905-15. [PubMed: 11560960]  [MGI Ref ID J:71611]

Solca C; Pandit B; Yu H; Tint GS; Patel SB. 2007. Loss of apolipoprotein E exacerbates the neonatal lethality of the Smith-Lemli-Opitz syndrome mouse. Mol Genet Metab 91(1):7-14. [PubMed: 17197219]  [MGI Ref ID J:121454]

Additional References

Dhcr7^tm1Gst related

Tint GS; Yu H; Shang Q; Xu G; Patel SB. 2006. The use of the Dhcr7 knockout mouse to accurately determine the origin of fetal sterols. J Lipid Res 47(7):1535-41. [PubMed: 16651660]  [MGI Ref ID J:112056]

Waage-Baudet H; Dunty WC Jr; Dehart DB; Hiller S; Sulik KK. 2005. Immunohistochemical and microarray analyses of a mouse model for the smith-lemli-opitz syndrome. Dev Neurosci 27(6):378-96. [PubMed: 16280635]  [MGI Ref ID J:103328]

Waage-Baudet H; Lauder JM; Dehart DB; Kluckman K; Hiller S; Tint GS; Sulik KK. 2003. Abnormal serotonergic development in a mouse model for the Smith-Lemli-Opitz syndrome: implications for autism. Int J Dev Neurosci 21(8):451-9. [PubMed: 14659996]  [MGI Ref ID J:100040]

Yu H; Wessels A; Chen J; Phelps AL; Oatis J; Tint GS; Patel SB. 2004. Late gestational lung hypoplasia in a mouse model of the Smith-Lemli-Opitz syndrome. BMC Dev Biol 4(1):1. [PubMed: 15005800]  [MGI Ref ID J:93296]

Yu H; Wessels A; Tint GS; Patel SB. 2005. Partial rescue of neonatal lethality of Dhcr7 null mice by a nestin promoter-driven DHCR7 transgene expression. Brain Res Dev Brain Res 156(1):46-60. [PubMed: 15862627]  [MGI Ref ID J:98266]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           AX11

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, heterozygous mice are bred to wildtype siblings or to C57BL/6J inbred mice. Homozygotes have abnormalities leading to perinatal death.
Mating System	+/+ sibling x Heterozygote         (Female x Male)
Diet Information	LabDiet® 5K52/5K67

Purchasing information

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

Pricing

Supply Details

Standard Supply

Repository-Live. A collection of over 1000 strains maintained as live colonies. Individual colonies are sized to meet current customer demand. Delivery for orders of 10 mice or less ranges on average from one to eight weeks; mice are generally shipped between four to six weeks of age with a maximum shipping age of ~nine weeks. Colony sizes do not generally support stringent age specifications for large volumes of mice; however custom orders and larger quantities of mice are easily arranged. Estimated ship dates for all orders provided within 48 hours of order placement.

Supply Notes

Usually shipped between four and eight weeks of age. This strain is included in the Induced Mutant Resource Colony collection.

Control Information

	Control
	Wild-type from the colony
	000664 C57BL/6J
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.

General Terms and Conditions

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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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