Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene (original) (raw)

Nature Genetics volume 16, pages 303–306 (1997)Cite this article

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.

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Author notes

  1. Robert S. Jackson and John W.M. Creemers: Equal contributors.

Authors and Affiliations

  1. Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge, CB22QQ, UK
    Robert S. Jackson
  2. Laboratory for Molecular Oncology, Center for Human Genetics, University ofLeuven and Flanders Interuniversity Institute for Biotechnology, Herestraat 49, B-3000, Leuven, Belgium
    John W.M. Creemers
  3. First Department of Medicine, Wakayama University of Medical Science, 27 Nanaban-cho, Wakayama, 640, Japan
    Shinya Ohagi
  4. Groupe d'Étude en Physiopathologie Endocrinienne, INSERM CJF 9208, Institut Cochin de Ge´ne´tique Mole´culaire, Universite Rene´ Descartes, Paris, France
    Marie-Laure Raffin-Sanson
  5. Departments of Medicine and Clinical Biochemistry, University of Cambridge, Cambridge, CB2 2QQ, UK
    Louise Sanders, Carl T. Montague & Stephen O'Rahilly
  6. Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, 4200 East 9th Avenue, Box B140, Denver, Colorado, 80262, USA
    John C. Hutton

Authors

  1. Robert S. Jackson
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  2. John W.M. Creemers
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  3. Shinya Ohagi
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  4. Marie-Laure Raffin-Sanson
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  5. Louise Sanders
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  6. Carl T. Montague
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  7. John C. Hutton
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  8. Stephen O'Rahilly
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Corresponding author

Correspondence toStephen O'Rahilly.

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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

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