Obesity and impaired prohormone processing associated with mutations in the human prohormone convertase 1 gene (original) (raw)
- Letter
- Published: 01 July 1997
- John W.M. Creemers2 na1,
- Shinya Ohagi3,
- Marie-Laure Raffin-Sanson4,
- Louise Sanders5,
- Carl T. Montague5,
- John C. Hutton6 &
- …
- Stephen O'Rahilly5
Nature Genetics volume 16, pages 303–306 (1997)Cite this article
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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
- Robert S. Jackson and John W.M. Creemers: Equal contributors.
Authors and Affiliations
- Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge, CB22QQ, UK
Robert S. Jackson - 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 - First Department of Medicine, Wakayama University of Medical Science, 27 Nanaban-cho, Wakayama, 640, Japan
Shinya Ohagi - 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 - Departments of Medicine and Clinical Biochemistry, University of Cambridge, Cambridge, CB2 2QQ, UK
Louise Sanders, Carl T. Montague & Stephen O'Rahilly - 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
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- Robert S. Jackson
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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
- Received: 13 May 1997
- Accepted: 04 June 1997
- Issue Date: 01 July 1997
- DOI: https://doi.org/10.1038/ng0797-303