Description

Strain Information

Type Coisogenic; Mutant Strain; Targeted Mutation; Additional information on Genetically Engineered Mutant Mice. Mating System +/+ sibling x Heterozygote         (Female x Male) Species laboratory mouse Generation ?+N1F2 (03-SEP-08)   Donating Investigator Iris Lindberg,   University of Maryland, Baltimore

Description
The following text reflects the phenotype reported by the donating investigator on a "129Sv" genetic background (probably "Taconic Sv129" (129S6/SvEvJ)). While heterozygotes are viable and fertile, mice homozygous for this mutation (7B2-null) die in prepubertal or pubertal ages (5 weeks) with severe cardio-respiratory failure, convulsions, and hypothermia. No transcripts are detected in brain tissue from the targeted gene. 7B2 null mice are unable to make an active form of prohormone convertase 2 (PC2) and have high circulating corticosterone. Homozygotes on the 129S genetic background exhibit Cushing's-like disease pathologies of liver, pancreas, and pituitary; including pituitary-dependent hyperadrenocorticosteronism, severe hypoglycemia, hyperproinsulinemia, adrenal hypertrophy, pituitary hypotrophy, and altered islet cell morphology. 7B2-null mice develop the disease from intermediate lobe ACTH hypersecretion (rather than from pituitary adenomas). Other abnormalities include thinning fur, thin tail, skeletal defects, dorsal and intraperitoneal adipose deposits, low blood sugar, fatty liver, and inability to synthesize glucagon. The donating investigator reports that null pups on the 129/SvEv genetic background are distinguishable by appearance, do not compete well for milk, and suggests thinning litters to 1-2 mice to obtain homozygotes. These mice may be useful in studies of corticosterone excess and its profound developmental effects, Cushing's disease, and other neuro-endocrine, obesity, or metabolism research.

It should be noted that the phenotype could vary from that originally described. We will modify the strain description if necessary as published results become available.

Development
A transposon-based gene targeting approach was designed to interrupt exon 3 of the targeted gene by random integration of a transposon and subsequent introduction of a neo cassette. The construct was electroporated into 129/SvEv embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts. The resulting chimeric males were crossed with 129/SvEv females. Heterozygous mice on this 129/SvEv genetic background were bred together for many generations prior to arrival at The Jackson Laboratory. Upon arrival, mutant mice were bred with 129S1/SvImJ (Stock No. 002448) for at least one generation to establish this colony.

Control Information

	Control
	Wild-type from the colony
	002448 129S1/SvImJ	(approximate)
Considerations for Choosing Controls

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms

Acth-Independent Macronodular Adrenal Hyperplasia; AIMAH - 5

5 Conditionally targeted allele(s)

View Mammalian Phenotype Terms

Mammalian Phenotype Terms

      assigned by genotype

Scg5^tm1Led/Scg5^tm1Led

        either: 129S6/SvEvTac or (involves: 129S6/SvEvTac * FVB) or (involves: 129S6/SvEvTac * C57BL/6)

• lethality-postnatal
• postnatal lethality (MGI Ref ID J:53349)
  • only about 11% survive to weaning
• adipose tissue phenotype
• abnormal adipose tissue distribution (MGI Ref ID J:53349)
  • surviving mice show abnormal fat deposition on the back and around the neck
  • retroperitoneal fat deposits as well
• behavior/neurological phenotype
• convulsive seizures (MGI Ref ID J:77510)
  • convulsions occur just before death
• polyphagia (MGI Ref ID J:77510)
• cardiovascular system phenotype
• abnormal cardiovascular system morphology (MGI Ref ID J:77510)
• dystrophic cardiac calcinosis (MGI Ref ID J:77510)
• enlarged heart (MGI Ref ID J:77510)
• hemorrhage (MGI Ref ID J:53349)
  • often significant bleeding into the abdomen
• hemothorax (MGI Ref ID J:53349)
• digestive/alimentary phenotype
• abnormal islet of Langerhans morphology (MGI Ref ID J:53349)
  • increased beta and non-beta endocrine cell mass in the pancreas
• islet cell hyperplasia (MGI Ref ID J:53349)
  • architecture of the islets is disrupted
• endocrine/exocrine gland phenotype
• abnormal gland morphology (MGI Ref ID J:53349)
• abnormal adrenal gland morphology (MGI Ref ID J:53349)
• adrenal cortical hyperplasia (MGI Ref ID J:53349)
• abnormal islet of Langerhans morphology (MGI Ref ID J:53349)
  • increased beta and non-beta endocrine cell mass in the pancreas
• islet cell hyperplasia (MGI Ref ID J:53349)
  • architecture of the islets is disrupted
• cryptorchism (MGI Ref ID J:77510)
  • undescended testes frequently
• small adenohypophysis (MGI Ref ID J:77510)
  • hypotrophy of the anterior pituitary
• growth/size phenotype
• decreased body size (MGI Ref ID J:53349)
  • severely runted at 4-5 weeks of age
• hematopoietic system phenotype
• spleen atrophy (MGI Ref ID J:53349)
  • spleen was 1/5 normal size with an abnormal architecture
  • part of a generalized lymphoid atrophy
• homeostasis/metabolism phenotype
• abnormal blood chemistry (MGI Ref ID J:77510)
  • increased lactate levels in plasma
• abnormal circulating insulin level (MGI Ref ID J:53349)
  • delayed conversion of proinsulin I and II with increased proinsulin levels
  • increased circulating levels of insulin-like material
• abnormal circulating magnesium level (MGI Ref ID J:77510)
  • levels are significantly decreased in plasma and heart while liver and brain levels are increased 2X
• decreased circulating glucagon level (MGI Ref ID J:53349)
  • mature glucagons is eliminated and only limited levels of intermediate products are found
• hypoglycemia (MGI Ref ID J:53349)
• increased circulating corticosterone level (MGI Ref ID J:53349)
  • 4X increase in serum corticosterone
• abnormal glucose homeostasis (MGI Ref ID J:77510)
  • high levels of free tissue glucose in the liver and decreased free glucose in muscle
• abnormal circulating insulin level (MGI Ref ID J:53349)
  • delayed conversion of proinsulin I and II with increased proinsulin levels
  • increased circulating levels of insulin-like material
• decreased circulating glucagon level (MGI Ref ID J:53349)
  • mature glucagons is eliminated and only limited levels of intermediate products are found
• hypoglycemia (MGI Ref ID J:53349)
• increased glycogen level (MGI Ref ID J:77510)
  • liver glycogen levels increased 5X
• abnormal urine chemistry (MGI Ref ID J:77510)
  • ketonegative urine
• decreased body temperature (MGI Ref ID J:77510)
  • hypothermia occurs in the hours just before death
• increased adrenocorticotropin level (MGI Ref ID J:53349)
  • levels were increased 10-20% in the pituitary
• immune system phenotype
• spleen atrophy (MGI Ref ID J:53349)
  • spleen was 1/5 normal size with an abnormal architecture
  • part of a generalized lymphoid atrophy
• liver/biliary system phenotype
• enlarged liver (MGI Ref ID J:77510)
  • significant hepatomegaly
• hepatic necrosis (MGI Ref ID J:77510)
• hepatic steatosis (MGI Ref ID J:77510)
  • yellow color to liver
  • severe fat vacuolation and abnormal liver architecture
• renal/urinary system phenotype
• abnormal urine chemistry (MGI Ref ID J:77510)
  • ketonegative urine
• reproductive system phenotype
• cryptorchism (MGI Ref ID J:77510)
  • undescended testes frequently
• respiratory system phenotype
• abnormal respiration (MGI Ref ID J:77510)
• respiratory distress (MGI Ref ID J:77510)
  • mice suffer from labored respiration in the last day before dying
  • experience shortness of breath just before death
• hemothorax (MGI Ref ID J:53349)
• skin/coat/nails phenotype
• abnormal hair growth (MGI Ref ID J:77510)
• alopecia (MGI Ref ID J:77510)
  • regional hair loss
• sparse hair (MGI Ref ID J:77510)
• abnormal skin condition (MGI Ref ID J:53349)
  • mice are often ecchymotic (easily bruised)
• pallor (MGI Ref ID J:53349)
  • mice are pale
• thin skin (MGI Ref ID J:53349)
  • thinning skin
• hyperkeratosis (MGI Ref ID J:53349)
  • hyperkeratosis
• thin dermal layer (MGI Ref ID J:53349)
  • dermal atrophy
• nervous system phenotype
• convulsive seizures (MGI Ref ID J:77510)
  • convulsions occur just before death
• small adenohypophysis (MGI Ref ID J:77510)
  • hypotrophy of the anterior pituitary

View Research Applications

Research Applications

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

Cardiovascular Research
Other (altered fat metabolism)

Developmental Biology Research
Perinatal Lethality (Homozygous)

Diabetes and Obesity Research
Hyperinsulinemia
Hypoglycemia

Endocrine Deficiency Research
Adrenal Cortex Defects
Adrenal Medulla Defects
Hypothalamus/Pituitary Defects

Internal/Organ Research
Adrenal Cortex Defects
Adrenal Medulla Defects

Metabolism Research
Lipid Metabolism

Research Tools
Cardiovascular Research
Diabetes and Obesity Research
Endocrine Deficiency Research
Internal/Organ Research
Metabolism Research

Genes & Alleles

Gene & Allele Information

Allele Symbol		Scg5tm1Led
Allele Name		targeted mutation 1, Philip Leder
Allele Type		Targeted (knock-out)
Common Name(s)		7B2 KO;
Mutation Made By		Philip Leder,   Harvard Medical School
Strain of Origin		129S6/SvEvTac
ES Cell Line Name		TC-1
ES Cell Line Strain		129S6/SvEvTac
Gene Symbol and Name		Scg5, secretogranin V
Chromosome		2
Gene Common Name(s)		7B2; AI325031; P7B2; SGNE1; SgV; Sgne-1; Sgne1; expressed sequence AI325031; secretory granule neuroendocrine protein 1, 7B2 protein;
Molecular Note		Insertion of a neomycin resistance cassette placed an artificial transposon after the eightieth base pair of exon 3 and disrupted the gene. Northern analysis of brain did not detect transcript in homozygous mice. [MGI Ref ID J:42189]

Genotyping

Genotyping Information

Genotyping Protocols

Generic Neo Melt Curve Analysis, MCA, vers. 1
NEOTD (Generic Neo), STD PCR, vers. 1
Scg5^tm1Led, SEP PCR, vers. 1

Helpful Links

Optimizing PCR Protocols

References

References

Selected Reference(s)

Sarac MS; Zieske AW; Lindberg I. 2002. The lethal form of Cushing's in 7B2 null mice is caused by multiple metabolic and hormonal abnormalities. Endocrinology 143(6):2324-32. [PubMed: 12021197]  [MGI Ref ID J:77510]

Westphal CH; Muller L; Zhou A; Zhu X; Bonner-Weir S; Schambelan M; Steiner DF; Lindberg I; Leder P. 1999. The neuroendocrine protein 7B2 is required for peptide hormone processing in vivo and provides a novel mechanism for pituitary Cushing's disease. Cell 96(5):689-700. [PubMed: 10089884]  [MGI Ref ID J:53349]

Additional References

Scg5^tm1Led related

Laurent V; Jaubert-Miazza L; Desjardins R; Day R; Lindberg I. 2004. Biosynthesis of proopiomelanocortin-derived peptides in prohormone convertase 2 and 7B2 null mice. Endocrinology 145(2):519-28. [PubMed: 14576186]  [MGI Ref ID J:88673]

Laurent V; Kimble A; Peng B; Zhu P; Pintar JE; Steiner DF; Lindberg I. 2002. Mortality in 7B2 null mice can be rescued by adrenalectomy: involvement of dopamine in ACTH hypersecretion. Proc Natl Acad Sci U S A 99(5):3087-92. [PubMed: 11854475]  [MGI Ref ID J:126986]

Peinado JR; Laurent V; Lee SN; Peng BW; Pintar JE; Steiner DF; Lindberg I. 2005. Strain-dependent influences on the hypothalamo-pituitary-adrenal axis profoundly affect the 7B2 and PC2 null phenotypes. Endocrinology 146(8):3438-44. [PubMed: 15878971]  [MGI Ref ID J:129821]

Rehfeld JF; Lindberg I; Friis-Hansen L. 2002. Progastrin processing differs in 7B2 and PC2 knockout animals: a role for 7B2 independent of action on PC2. FEBS Lett 510(1-2):89-93. [PubMed: 11755537]  [MGI Ref ID J:73621]

Sarac MS; Windeatt S; Castro MG; Lindberg I. 2002. Intrapituitary adenoviral administration of 7B2 can extend life span and reverse endocrinological deficiencies in 7B2 null mice. Endocrinology 143(6):2314-23. [PubMed: 12021196]  [MGI Ref ID J:77509]

Vishnuvardhan D; Connolly K; Cain B; Beinfeld MC. 2000. PC2 and 7B2 null mice demonstrate that PC2 is essential for normal pro-CCK processing. Biochem Biophys Res Commun 273(1):188-91. [PubMed: 10873584]  [MGI Ref ID J:62889]

Westphal CH; Leder P. 1997. Transposon-generated 'knock-out' and 'knock-in' gene-targeting constructs for use in mice. Curr Biol 7:530-3. [PubMed: 9210379]  [MGI Ref ID J:42189]

Health & husbandry

Health & Colony Maintenance Information

Animal Health Reports

Room Number           AX11

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, these mice are bred as heterozygotes. The published phenotype of homozygous mice (on a "129Sv" genetic background (probably "Taconic Sv129" (129S6/SvEvJ)) die around 5 weeks of age. The donating investigator reports that null pups are distinguishable by appearance, do not compete well for milk, and suggests thinning litters to 1-2 mice to obtain homozygotes.
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
	002448 129S1/SvImJ	(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.

General Terms and Conditions

See Terms of Use

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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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