title: A nonsense loss-of-function mutation in PCSK1 contributes to dominantly inherited human obesity.
abstract: BACKGROUND
  A significant proportion of severe familial forms of obesity remain genetically elusive. Taking advantage of our unique cohort of multigenerational obese families, we aimed to assess the contribution of rare mutations in 29 common obesity-associated genes to familial obesity, and to evaluate in these families the putative presence of nine known monogenic forms of obesity.
  
  
  METHODS
  Through next-generation sequencing, we sequenced the coding regions of 34 genes involved in polygenic and/or monogenic forms of obesity in 201 participants (75 normal weight individuals, 54 overweight individuals and 72 individuals with obesity class I, II or III) from 13 French families. In vitro functional analyses were performed to investigate the mutation PCSK1-p.Arg80* which was identified in a family.
  
  
  RESULTS
  A novel heterozygous nonsense variant in PCSK1 (p.Arg80*), encoding a propeptide truncated to less than two exons (out of 14), was found to co-segregate with obesity in a three-generation family. We demonstrated that this mutation inhibits PCSK1 enzyme activity and that this inhibition most likely does not involve a strong physical interaction. Furthermore, both mutations PCSK1-p.Asn180Ser and POMC-p.Phe144Leu, which had previously been reported to be associated with severe obesity, were also identified in this study, but did not co-segregate with obesity. Finally, we did not identify any rare mutations co-segregating with obesity in common obesity susceptibility genes, except for CADM2 and QPCTL, where we found two novel variants (p.Arg81His and p.Leu98Pro, respectively) in three obese individuals.
  
  
  CONCLUSIONS
  We showed for the first time that a nonsense mutation in PCSK1 was likely to cause dominantly inherited human obesity, due to the inhibiting properties of the propeptide fragment encoded by the null allele. Furthermore, the present family sequencing design challenged the contribution of previously reported mutations to monogenic or at least severe obesity.
authors.affiliation: 1] CNRS-UMR8199, Institut de Biologie de Lille, Lille Pasteur Institute, Lille, France [2] Lille 2 University, Lille, France [3] European Genomic Institute for Diabetes (EGID), Lille, France.
authors.forename: J
authors.initials: J
authors.lastname: Philippe
authors.affiliation: Laboratory for Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: P
authors.initials: P
authors.lastname: Stijnen
authors.affiliation: 1] CNRS-UMR8199, Institut de Biologie de Lille, Lille Pasteur Institute, Lille, France [2] Lille 2 University, Lille, France [3] European Genomic Institute for Diabetes (EGID), Lille, France [4] Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada.
authors.forename: D
authors.initials: D
authors.lastname: Meyre
authors.affiliation: 1] CNRS-UMR8199, Institut de Biologie de Lille, Lille Pasteur Institute, Lille, France [2] Lille 2 University, Lille, France [3] European Genomic Institute for Diabetes (EGID), Lille, France.
authors.forename: F
authors.initials: F
authors.lastname: De Graeve
authors.affiliation: 1] CNRS-UMR8199, Institut de Biologie de Lille, Lille Pasteur Institute, Lille, France [2] Lille 2 University, Lille, France [3] European Genomic Institute for Diabetes (EGID), Lille, France.
authors.forename: D
authors.initials: D
authors.lastname: Thuillier
authors.affiliation: 1] CNRS-UMR8199, Institut de Biologie de Lille, Lille Pasteur Institute, Lille, France [2] Lille 2 University, Lille, France [3] European Genomic Institute for Diabetes (EGID), Lille, France.
authors.forename: J
authors.initials: J
authors.lastname: Delplanque
authors.affiliation: Genoscope, Evry, France.
authors.forename: G
authors.initials: G
authors.lastname: Gyapay
authors.affiliation: 1] CNRS-UMR8199, Institut de Biologie de Lille, Lille Pasteur Institute, Lille, France [2] Lille 2 University, Lille, France [3] European Genomic Institute for Diabetes (EGID), Lille, France.
authors.forename: O
authors.initials: O
authors.lastname: Sand
authors.affiliation: Laboratory for Biochemical Neuroendocrinology, Department of Human Genetics, KU Leuven, Leuven, Belgium.
authors.forename: J W
authors.initials: JW
authors.lastname: Creemers
authors.affiliation: 1] CNRS-UMR8199, Institut de Biologie de Lille, Lille Pasteur Institute, Lille, France [2] Lille 2 University, Lille, France [3] European Genomic Institute for Diabetes (EGID), Lille, France [4] Department of Genomics of Common Disease, School of Public Health, Imperial College London, Hammersmith Hospital, London, United Kingdom.
authors.forename: P
authors.initials: P
authors.lastname: Froguel
authors.affiliation: 1] CNRS-UMR8199, Institut de Biologie de Lille, Lille Pasteur Institute, Lille, France [2] Lille 2 University, Lille, France [3] European Genomic Institute for Diabetes (EGID), Lille, France.
authors.forename: A
authors.initials: A
authors.lastname: Bonnefond
mesh_terms: D018389:Codon, Nonsense / Q000235:genetics*; D005260:Female; D005602:France / Q000453:epidemiology; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009765:Obesity / Q000453:epidemiology / Q000235:genetics*; D010375:Pedigree; D045664:Proprotein Convertase 1 / Q000235:genetics*; D044465:White People / Q000235:genetics*
chemical_list: D018389:Codon, Nonsense; C587576:PCSK1 protein, human; D045664:Proprotein Convertase 1