Heterozygous Mutations Causing Partial Prohormone Convertase 1 Deficiency Contribute to Human Obesity

  1. David Meyre2,15
  1. 1Department of Human Genetics, University of Leuven, Leuven, Belgium
  2. 2Centre National de la Recherche Scientifique (CNRS) 8199, Lille North of France University, Pasteur Institute, Lille, France
  3. 3Department of Nutrition, Hospital University, Lille, France
  4. 4Department of Medical Genetics, University of Antwerp, Antwerp, Belgium
  5. 5Leibniz Institute for Age Research, Fritz Lipmann Institute, Jena, Germany
  6. 6INSERM U563, Children’s Hospital, Centre Hospitalier Universitaire, Toulouse, France
  7. 7INSERM U1018, Villejuif, France
  8. 8University Paris Sud 11, UMRS 1018, Villejuif, France
  9. 9Department of Epidemiology and Biostatistics, and MRC-HPA Centre for Environment and Health, Imperial College London, London, U.K.
  10. 10Department of Child and Adolescent Health, National Public Health Institute, Biocenter Oulu, University of Oulu, Oulu, Finland
  11. 11Department of Endocrinology, Antwerp University Hospital, Antwerp, Belgium
  12. 12Department of Surgery and Internal Medicine, Clinic Lindberg, Winterthur, Switzerland
  13. 13INSERM U859, Lille North of France University, Lille, France
  14. 14Department of Genomics of Common Disease, School of Public Health, Imperial College London, London, U.K.
  15. 15Department of Clinical Epidemiology & Biostatistics, McMaster University, Hamilton, Ontario, Canada
  1. Corresponding authors: John W.M. Creemers, john.creemers{at}, and Philippe Froguel, p.froguel{at}


Null mutations in the PCSK1 gene, encoding the proprotein convertase 1/3 (PC1/3), cause recessive monogenic early onset obesity. Frequent coding variants that modestly impair PC1/3 function mildly increase the risk for common obesity. The aim of this study was to determine the contribution of rare functional PCSK1 mutations to obesity. PCSK1 exons were sequenced in 845 nonconsanguineous extremely obese Europeans. Eight novel nonsynonymous PCSK1 mutations were identified, all heterozygous. Seven mutations had a deleterious effect on either the maturation or the enzymatic activity of PC1/3 in cell lines. Of interest, five of these novel mutations, one of the previously described frequent variants (N221D), and the mutation found in an obese mouse model (N222D), affect residues at or near the structural calcium binding site Ca-1. The prevalence of the newly identified mutations was assessed in 6,233 obese and 6,274 lean European adults and children, which showed that carriers of any of these mutations causing partial PCSK1 deficiency had an 8.7-fold higher risk to be obese than wild-type carriers. These results provide the first evidence of an increased risk of obesity in heterozygous carriers of mutations in the PCSK1 gene. Furthermore, mutations causing partial PCSK1 deficiency are present in 0.83% of extreme obesity phenotypes.

  • Received March 4, 2011.
  • Accepted October 24, 2011.

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