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

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          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.

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          Author and article information

          Journal
          Nat Genet
          Nature genetics
          Springer Science and Business Media LLC
          1061-4036
          1061-4036
          Jul 1997
          : 16
          : 3
          Affiliations
          [1 ] Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge, UK.
          Article
          10.1038/ng0797-303
          9207799
          9a137f22-cb8e-4df5-97e0-407f793441b7
          History

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