title: A targeted deletion/insertion in the mouse Pcsk1 locus is associated with homozygous embryo preimplantation lethality, mutant allele preferential transmission and heterozygous female susceptibility to dietary fat.
abstract: Proprotein convertase 1 (PC1) is a neuroendocrine proteinase involved in the proteolytic activation of precursors to hormones and neuropeptides. To determine the physiological importance of PC1, we produced a mutant mouse from embryonic stem cells in which its locus (Pcsk1) had been inactivated by homologous recombination. The inactivating mutation consisted of a 32.7-kb internal deletion and a 1.8 kb insertion of the bacterial neomycin resistance gene (neo) under the mouse phosphoglycerate kinase 1 protein (PGKneo). Intercross of Pcsk1(+/-) mice produced no Pcsk1(-/-) offspring or blastocysts; in addition, more than 80% of the offspring were Pcsk1(+/-). These observations suggested that the mutation caused preimplantation lethality of homozygous embryos and preferential transmission of the mutant allele. Interestingly, RT-PCR analysis on RNA from endocrine tissues from Pcsk1(+/-) mice revealed the presence of aberrant transcripts specifying the N-terminal half of the PC1 propeptide fused to neo gene product. Mass spectrometric profiles of proopiomelanocortin-derived peptides in the anterior pituitary were similar between Pcsk1(+/-) and Pcsk1(+/+) mice, but significantly different between male and female mice of the same genotype. Relative to their wild-type counterparts, female mutant mice exhibited stunted growth under a low fat diet, and catch-up growth under a high-fat diet. The complex phenotype exhibited by this Pcsk1 mutant mouse model may be due to PC1 deficiency aggravated by expression of aberrant gene products from the mutant allele.
authors.affiliation: Ottawa Health Research Institute and The Ottawa Hospital, 725 Parkdale Avenue, Ottawa, Ontario, Canada. mmbikay@ohri.ca
authors.forename: Majambu
authors.initials: M
authors.lastname: Mbikay
authors.forename: Gilles
authors.initials: G
authors.lastname: Croissandeau
authors.forename: Francine
authors.initials: F
authors.lastname: Sirois
authors.forename: Younes
authors.initials: Y
authors.lastname: Anini
authors.forename: Janice
authors.initials: J
authors.lastname: Mayne
authors.forename: Nabil G
authors.initials: NG
authors.lastname: Seidah
authors.forename: Michel
authors.initials: M
authors.lastname: Chrétien
mesh_terms: D000483:Alleles; D000818:Animals; D001755:Blastocyst; D004041:Dietary Fats; D005260:Female; D017353:Gene Deletion; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006720:Homozygote; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D045664:Proprotein Convertase 1 / Q000235:genetics* / Q000502:physiology*
chemical_list: D004041:Dietary Fats; C473656:Pcsk1 protein, mouse; D045664:Proprotein Convertase 1