title: Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene.
abstract: Human obesity has an inherited component, but in contrast to rodent obesity, precise genetic defects have yet to be defined. A mutation of carboxypeptidase E (CPE), an enzyme active in the processing and sorting of prohormones, causes obesity in the fat/fat mouse. We have previously described a women with extreme childhood obesity (Fig. 1), abnormal glucose homeostasis, hypogonadotrophic hypogonadism, hypocortisolism and elevated plasma proinsulin and pro-opiomelanocortin (POMC) concentrations but a very low insulin level, suggestive of a defective prohormone processing by the endopeptidase, prohormone convertase 1 (PC1; ref. 4). We now report this proband to be a compound heterozygote for mutations in PC1. Gly-->Arg483 prevents processing of proPC1 and leads to its retention in the endoplasmic reticulum (ER). A-->C+4 of the intro-5 donor splice site causes skipping of exon 5 leading to loss of 26 residues, a frameshift and creation of a premature stop codon within the catalytic domain. PC1 acts proximally to CPE in the pathway of post-translational processing of prohormones and neuropeptides. In view of the similarity between the proband and the fat/fat mouse phenotype, we infer that molecular defects in prohormone conversion may represent a generic mechanism for obesity, common to humans and rodents.
authors.affiliation: Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge, UK.
authors.forename: R S
authors.initials: RS
authors.lastname: Jackson
authors.forename: J W
authors.initials: JW
authors.lastname: Creemers
authors.forename: S
authors.initials: S
authors.lastname: Ohagi
authors.forename: M L
authors.initials: ML
authors.lastname: Raffin-Sanson
authors.forename: L
authors.initials: L
authors.lastname: Sanders
authors.forename: C T
authors.initials: CT
authors.lastname: Montague
authors.forename: J C
authors.initials: JC
authors.lastname: Hutton
authors.forename: S
authors.initials: S
authors.lastname: O'Rahilly
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D016282:Aspartic Acid Endopeptidases / Q000235:genetics* / Q000378:metabolism; D016466:CHO Cells; D043423:Carboxypeptidase H; D002268:Carboxypeptidases / Q000378:metabolism; D006224:Cricetinae; D004721:Endoplasmic Reticulum / Q000201:enzymology; D005260:Female; D005455:Fluorescent Antibody Technique; D006579:Heterozygote; D006801:Humans; D051379:Mice; D008815:Mice, Inbred Strains; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D009154:Mutation; D009765:Obesity / Q000201:enzymology / Q000235:genetics*; D016133:Polymerase Chain Reaction; D018807:Polymorphism, Single-Stranded Conformational; D045664:Proprotein Convertase 1; D043484:Proprotein Convertases; D011498:Protein Precursors / Q000378:metabolism; D011499:Protein Processing, Post-Translational; D012326:RNA Splicing; D012333:RNA, Messenger / Q000235:genetics; D014162:Transfection
chemical_list: D011498:Protein Precursors; D012333:RNA, Messenger; D002268:Carboxypeptidases; D043423:Carboxypeptidase H; D043484:Proprotein Convertases; C473656:Pcsk1 protein, mouse; D045664:Proprotein Convertase 1; D016282:Aspartic Acid Endopeptidases