C57BL/6J-Pcsk1^N222D/J

Stock number: 006699
Product name: Pc1 KO
Research areas: Cardiovascular Research, Diabetes and Obesity Research, Endocrine Deficiency Research, Metabolism Research, Neurobiology Research, Research Tools

Description

Homozygotes for this ENU induced proprotein convertase subtilisin/kexin type 1 mutation exhibit obesity, abnormal proinsulin processing and multiple endocrinological defects, and are a model for human PC1 deficiency.

Detailed 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).

Allele

Symbol: Pcsk1^N222D
Name: N222D
MGI accession ID: MGI:3629669
Generation method: Chemically induced (ENU)
Marker symbol: Pcsk1
Marker name: proprotein convertase subtilisin/kexin type 1
Chromosome: 13
Strain of origin: C57BL/6
Molecular note: An A to G transition resulted in an asparagines to aspartic acid at codon 222.