These mice harbor a knock-out mutation of the Eif2ak3 gene and may serve as a mouse model of Wolcott-Rallison syndrome.
David Ron, NYU School of Medicine
Of note, Perk-mutant mice may also be useful along with other Eif2ak-mutant mice from the same investigator, including Eif2ak4-knock-out mice (Stock No. 008240) and Eif2ak4-floxed mice (Stock No. 008452).
These mice harbor a targeted mutation of the Eif2ak3 (eukaryotic translation initiation factor 2 alpha kinase 3 [also called Perk]) locus that abolishes endogenous gene expression. To date (Feb 2010), the donating investigator has not been able to generate homozygous mice on a C57BL/6J congenic background. The following phenotype describes mice on a mixed albino Swiss Webster;129/SvEv genetic background. Heterozygous mice are viable and fertile. Homozygous (Perk-/-) mice appear runty within a few days of birth and develop a rapid and progressive decline in endocrine and exocrine pancreatic function. This results in a complex pleiotropic phenotype including hyperglycemia, exocrine pancreatic insufficiency, diabetes, growth retardation, inability to breed, and early mortality. The phenotype of the Perk-/- mice is very similar to that observed in humans with Wolcott-Rallison syndrome; the consistent feature of which is severe diabetes mellitus developing in infancy. Heterozygous mice are viable and fertile with a mild defect in glycemic control (mildly impaired glucose tolerance). Perk-mutant mice may be useful in studying eIF2 (eukaryotic initiation factor 2) phosphorylation in response to environmental or endoplasmic reticulum stresses, exocrine pancreatic dysfunction, stress signals initiated by protein malfolding, and infantile diabetes mellitus.
In an attempt to offer alleles on well-characterized or multiple genetic backgrounds, alleles are frequently moved to a genetic background different from that on which an allele was first characterized. It should be noted that the phenotype could vary from that originally described. We may modify the strain description if necessary as published results become available.
A targeting vector was designed by the laboratory of Dr. David Ron (New York University School of Medicine) to replace a 1.6 kbp region of the targeted gene (encoding the transmembrane domain) with a reverse-oriented PGK-Neo cassette. The construct was electroporated into 129S6/SvEvTac-derived W4 embryonic stem (ES) cells. Correctly targeted ES cells were injected into recipient blastocysts and chimeric males were bred with "black Swiss Webster" females to generate the mutant colony. The Perk-mutant colony was subsequently maintained on a mixed albino Swiss Webster;129/SvEv genetic background for many generations and then sent to Dr. Gokhan S. Hotamisligil (Harvard University School of Public Health). There, Perk-mutant mice were reportedly backcrossed to C57BL6/J mice for at least eight generations (see SNP results below) prior to sending males to The Jackson Laboratory Repository in 2013. Upon arrival, heterozygous mice were bred to C57BL/6J inbred mice (Stock No. 000664) for at least one generation to establish the colony.
In 2013, a 32 SNP (single nucleotide polymorphism) panel analysis, with 27 markers covering all 19 chromosomes and the X chromosome, as well as 5 markers that distinguish between the C57BL/6J and C57BL/6N substrains, was performed on the first generation rederived living colony at The Jackson Laboratory Repository. While all 27 markers throughout the genome suggested a C57BL/6 genetic background, 3 of 5 markers that determine C57BL/6J from C57BL/6N were found to be segregating. These data suggest that the mice sent to The Jackson Laboratory Repository were on a mixed C57BL/6N;C57BL/6J genetic background.
|Allele Name||targeted mutation 1, David Ron|
|Allele Type||Targeted (Null/Knockout)|
|Allele Synonym(s)||perk -|
|Gene Symbol and Name||Eif2ak3, eukaryotic translation initiation factor 2 alpha kinase 3|
|Gene Synonym(s)||AI427929; PEK; PERK; WRS; expressed sequence AI427929|
|Strain of Origin||129S6/SvEvTac|
|Molecular Note||A neomycin selection cassette replaced 1.6 kb of DNA containing the transmembrane domain. Northern blot analysis demonstrated that at least 10-fold less transcript was produced from this allele that the wild-type. However, western blot analysis on cells derived from homozygous mice confirmed that no detectable protein was expressed from this allele.|
|Mutations Made By|| |
David Ron, NYU School of Medicine
When maintaining a live colony, heterozygous mice may be bred together or to wildtype siblings. The donating investigator has not been able to generate homozygous mice on a C57BL/6J congenic background to date (February 2010). On a mixed albino Swiss Webster;129/SvEv genetic background, homozygous mice appear runty within days of birth. To increase the viability of homozygous pups prior to weaning, one may remove normal sized pups (likely heterozygous or wildtype siblings) from the litter.
The average number of mice provided from recovery of our cryopreserved strains is 10. The total number of animals provided,
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