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 Chemically Induced Mutation; Coisogenic; Mutant Strain; Additional information on Genetically Engineered and Mutant Mice. Visit our online Nomenclature tutorial. Species laboratory mouse Generation N1F1pN1 Generation Definitions   Donating Investigator Nicholas Gekakis,   The Scripps Research Institute

Description
Mice homozygous for this ENU-induced "Pc1^N222D" mutation are viable and fertile, although the donating investigator reports that homozygous breeders have diminished reproductive performance. Unlike mice homozygous for the traditional knockout allele, Pc1^N222D homozygotes are not runted. Homozygous mice exhibit obesity, abnormal proinsulin processing and multiple endocrinological defects. Increased energy intake and a more efficient metabolism contribute to the obesity. Defective proinsulin processing leads to glucose intolerance, but neither insulin resistance nor diabetes develop despite obesity. Obesity is associated with impaired autocatalytic and neuropeptide processing. These mutant mice are a model of human PC1 deficiency, and may be useful in studying obesity, fat metabolism, propeptide processing, and neuroendocrinology.

Development
Following multidose N-ethyl-N-nitrosourea (ENU) treatments to induce mutations in founder C57BL/6J mice, a forward genetic screen was utilized to identify a hyperproinsulinemic, obese family of mice. Using a candidate gene approach, a point mutation in the coding sequence of the prohormone convertase 1 (Pc1 or Pcsk1) gene. Sequencing of this gene identified an adenine-to-guanine transition, leading to an amino acid change from asparagine to aspartic acid at codon 222 of the protein (N222D).

Control Information

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

Related Strains

Strains carrying other alleles of Pcsk1

006327

STOCK Pcsk1tm1Dfs/J

View Strains carrying other alleles of Pcsk1     (1 strain)

Phenotype

Phenotype Information

View Related Disease (OMIM) Terms

Related Disease (OMIM) Terms provided by MGI

Obesity - 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

Pcsk1^N222D/Pcsk1^N222D

        C57BL/6-Pcsk1^N222D

• growth/size phenotype
• increased body weight
  • from 8 weeks of age, mice display elevated body weight compared to wild-type littermates; at 6 months of age, males are 32% heavier than wild-type littermates and females are 68% heavier   (MGI Ref ID J:109531)
• • obese
    • from 8 weeks of age and during the length of the study, mice remain more obese than wild-type controls on a breeder diet (21% calories from fat)   (MGI Ref ID J:109531)
• behavior/neurological phenotype
• polyphagia
  • over a week, mice eat 13% more than wild-type controls   (MGI Ref ID J:109531)
• homeostasis/metabolism phenotype
• abnormal metabolism
  • mice show a trend to decreased (10%) metabolic rate vs controls   (MGI Ref ID J:109531)
• increased circulating leptin level
  • at 26 weeks, leptin levels are increased in females 94 mg/ml vs control 13 mg/ml)   (MGI Ref ID J:109531)
• endocrine/exocrine gland phenotype
• decreased testis weight
  • testes show a significant decrease in weight   (MGI Ref ID J:109531)
• adipose tissue phenotype
• abnormal inguinal fat pad morphology
  • there is massive adipocyte hypertrophy with a 10- to 100-fold increase in adipocyte volume compared to wild-type littermates   (MGI Ref ID J:109531)
• increased white adipose tissue amount
  • weight difference is due to increase in fat mass in males and females on all diets tested   (MGI Ref ID J:109531)
• reproductive system phenotype
• decreased testis weight
  • testes show a significant decrease in weight   (MGI Ref ID J:109531)
• reduced fertility
  • males and females reproduce but less frequently compared to controls   (MGI Ref ID J:109531)
• muscle phenotype
• decreased skeletal muscle mass
  • on normal chow diet, mice exhibit muscle mass reduction   (MGI Ref ID J:109531)
• increased skeletal muscle mass
  • on a breeder diet, mice show increased muscularity   (MGI Ref ID J:109531)

View Research Applications

Research Applications

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

Cardiovascular Research
Other
      altered fat metabolism

Diabetes and Obesity Research
Hyperinsulinemia
Impaired Insulin Processing
Obesity Without Diabetes

Endocrine Deficiency Research

Metabolism Research

Neurobiology Research
Metabolic Defects

Research Tools
Diabetes and Obesity Research
Endocrine Deficiency Research
Metabolism Research

Genes & Alleles

Gene & Allele Information provided by MGI

Allele Symbol		Pcsk1N222D
Allele Name		N222D
Allele Type		Chemically induced (ENU)
Common Name(s)		Pc1N222D;
Mutation Made By		Nicholas Gekakis,   The Scripps Research Institute
Strain of Origin		C57BL/6
Gene Symbol and Name		Pcsk1, proprotein convertase subtilisin/kexin type 1
Chromosome		13
Gene Common Name(s)		BMIQ12; NEC1; Nec-1; Nec1; PC1; PC3; Phpp-1; SPC3; neuroendocrine convertase 1; prehormone processing proteinase; prohormone convertase 1/3;
Molecular Note		An A to G transition resulted in an asparagines to aspartic acid at codon 222. [MGI Ref ID J:109531]

Genotyping

Genotyping Information

Genotyping Protocols

Pcsk1^N222D, Pyrosequencing

Helpful Links

Genotyping resources and troubleshooting

References

References provided by MGI

Selected Reference(s)

Lloyd DJ; Bohan S; Gekakis N. 2006. Obesity, hyperphagia and increased metabolic efficiency in Pc1 mutant mice. Hum Mol Genet 15(11):1884-93. [PubMed: 16644867]  [MGI Ref ID J:109531]

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

Animal Health Reports

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

Colony Maintenance

Breeding & Husbandry	When maintaining a live colony, homozygous mice are bred. The donating investigator reports that homozygous breeders have diminished reproductive performance.

Purchasing information

Pricing, Supply Level & Notes, Controls

General Supply Notes

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