Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene

Nat Genet. 1997 Jul;16(3):303-6. doi: 10.1038/ng0797-303.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Aspartic Acid Endopeptidases / genetics*
  • Aspartic Acid Endopeptidases / metabolism
  • CHO Cells
  • Carboxypeptidase H
  • Carboxypeptidases / metabolism
  • Cricetinae
  • Endoplasmic Reticulum / enzymology
  • Female
  • Fluorescent Antibody Technique
  • Heterozygote
  • Humans
  • Mice
  • Mice, Inbred Strains
  • Microscopy, Fluorescence
  • Molecular Sequence Data
  • Mutation*
  • Obesity / enzymology
  • Obesity / genetics*
  • Polymerase Chain Reaction
  • Polymorphism, Single-Stranded Conformational
  • Proprotein Convertase 1*
  • Proprotein Convertases
  • Protein Precursors / metabolism
  • Protein Processing, Post-Translational
  • RNA Splicing
  • RNA, Messenger / genetics
  • Transfection


  • Protein Precursors
  • RNA, Messenger
  • Carboxypeptidases
  • Carboxypeptidase H
  • Proprotein Convertases
  • Pcsk1 protein, mouse
  • Proprotein Convertase 1
  • Aspartic Acid Endopeptidases