Abstract
Human obesity has an inherited component, but in contrast to rodent obesity, precise genetic defects have yet to be defined1. A mutation of carboxypeptidase E (CPE), an enzyme active in the processing and sorting of prohormones, causes obesity in the fat/fat mouse2,3. We have previously described a woman 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 proPd and leads to its retention in the endoplasmic reticulum (ER). A→C+4 of the intron-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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Spiegelman, B.M. & Flier, J.S. Adipogenesis and obesity: founding out the big picture. Cell 87, 377–389 (1996).
Naggert, J.K. et al. Hyperproinsulinaemia in obese fat/fat mice associated with a carboxypeptidase E mutation which reduces enzyme activity. Nature Genet. 10, 135–142 (1995).
Cool, D.R. et al. Carboxypeptidase E is a regulated secretory pathway sorting receptor: genetic obliteration leads to endocrine disorders in Cpefat mice. Cell 88, 73–83 (1997).
O'Rahilly, S. et al. Impaired processing of prohormones associated with abnormalities of glucose homeostasis and adrenal function. N. Engl. J. Med. 333, 1386–1390 (1995).
Orita, M., Iwahana, H., Kanazawa, H., Hayashi, K. & Sekiya, T. Detection of polymorphisms of human DNA by gel electrophoresis as single-strand conformation polymorphisms. Proc. Natl. Acad. Sci. USA. 86, 2766–2770 (1989).
Ohagi, S. et al. Human prohormone convertase 3 gene: exon-intron organization and molecular scanning for mutations in Japanese subjects with NIDDM. Diabetes 45, 897–901 (1996).
Mount, S. A catalogue of splice junction sequences. Nucleic Adds Res. 10, 459–472 (1982).
Krawczak, M., Reiss, J. & Cooper, N. The mutational spectum of single base-pair substitutions in mRNA splice junctions of human genes: causes and consequences. Hum. Genet. 90, 41–54 (1992).
Scriver, C.R., Beaudet, A.L., Sly, W. S. & Valle, D. The Metabolic and Molecular Basis of Inherited Disease. 269–270 McGraw-Hill, New York,(1995).
Zhou, Y. & Lindberg, I. Purification and characterization of the prohormone convertase PC1 (PC3). J. Biol. Chem. 268, 5615–5623 (1993).
Creemers, J.W. et al. Endoproteolytic cleavage of its propeptide is a prerequisite for the efficient transport of f urin out of the endoplasmic reticulum. J. Biol. Chem. 270, 2695–702 (1995).
Taylor, N.A., Shennan, K.I.J., Cutler, D.F. & Docherty, K. Mutations within the propeptide, the primary cleavage site or the catalytic site, or deletion of C-terminal sequences, prevents secretion of proPC2 from transfected COS-7 cells. Biochem. J. 321, 367–373 (1997).
Davidson, H.W., Rhodes, C.J. & Mutton, J.C. Intraorganellar calcium and pH control proinsulin cleavage in the pancreatic cell via two distinct site-specific endopeptidases. Nature 333, 93–96 (1988).
Rouille, Y. et al. Proteolytic processing mechanisms in the biosynthesis of neuroendocrine peptides: the subtilisin-like proprotein convertases. Front. Endocrinol. 16, 322–361 (1995).
Fricker, L.D., Berman, Y.L., Leiter, E.H. & Devi, L. A. Carboxypeptidase E activity is deficient in mice with the fat mutation. J. Biol. Chem. 271, 30619–30624 (1996).
Fan, W., Boston, B.A., Kesterson, R.A., Hruby, V.J. & Cone, R.D. Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 385, 165–168 (1997).
Huszar, D. et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88, 131–141 (1997).
Turton, M.D. et al. A role for glucagon-like peptide-1 in the central regulation of feeding. Nature 379, 69–72 (1996).
Zaidi, F.K. et al. Homozygosity for a common polymorphism in the islet-specific promotor of the glucokinase gene is associated with a reduced early insulin response to oral glucose in pregnant women. Diabet Med. 14, 228–234 (1997).
Creemers, J.W., Roebroek, A.J. & Van-de-Ven, W.J. Expression in human lung tumor cells of the proprotein processing enzyme PC1/PC3. Cloning and primary sequence of a 5kb cDNA. FEBS Lett. 300, 82–88 (1992).
Creemers, J.W. et al. Modulation of furin-mediated proprotein processing activity by site-directed mutagenesis. Biol. Chem. 268, 21826–21834 (1993).
Creemers, J.W. et al. Identification of a transferable sorting domain for the regulated pathway in the prohormone convertase PC2. J. Biol. Chem. 271, 25284–25291 (1997).
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Jackson, R., Creemers, J., Ohagi, S. et al. Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene. Nat Genet 16, 303–306 (1997). https://doi.org/10.1038/ng0797-303
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1038/ng0797-303
This article is cited by
-
Rare genetic forms of obesity in childhood and adolescence: A narrative review of the main treatment options with a focus on innovative pharmacological therapies
European Journal of Pediatrics (2024)
-
The melanocortin action is biased toward protection from weight loss in mice
Nature Communications (2023)
-
The discovery of human monogenic obesity
Nature Reviews Endocrinology (2023)
-
Rare genetic forms of obesity in childhood and adolescence, a comprehensive review of their molecular mechanisms and diagnostic approach
European Journal of Pediatrics (2023)
-
The genetics of obesity: from discovery to biology
Nature Reviews Genetics (2022)