title: Mutations in the amino-terminal region of proopiomelanocortin (POMC) in patients with early-onset obesity impair POMC sorting to the regulated secretory pathway.
abstract: BACKGROUND
  Mutations in the proopiomelanocortin (POMC) gene that impair the synthesis or structure of POMC-derived peptides predispose to human obesity.
  
  
  OBJECTIVE
  Our objective was to identify and characterize novel mutations in the POMC gene found in patients with early-onset obesity.
  
  
  METHODS
  The POMC gene was screened in 500 patients with severe early-onset obesity. The biosynthesis, processing, sorting, and secretion of wild-type POMC and two newly identified POMC mutants was studied using metabolic labeling, Western blotting, and immunoassay analysis of lysates and conditioned media of transiently transfected beta-TC3 cells.
  
  
  RESULTS
  Two novel heterozygous missense mutations in POMC (C28F and L37F) were identified in unrelated probands with early-onset obesity and their overweight or obese family members. Both mutations lie in a region of the N terminus of POMC that has been suggested to be involved in its sorting to the regulated secretory pathway. Metabolic labeling studies indicate that whereas the mutations do not reduce intracellular levels of POMC, both mutations (C28F>L37F) impair the ability of POMC to be processed to generate bioactive products. Studies of the secretion of POMC products suggest, particularly with C28F, that the impaired propeptide processing of these mutations results, at least in part, from a mistargeting of mutant POMC to the constitutive rather than the regulated secretory pathway.
  
  
  CONCLUSIONS
  These mutations in patients with early-onset obesity represent a novel molecular mechanism of human POMC deficiency whereby naturally occurring mutations in its N-terminal sequence impair the ability of POMC to enter the trafficking pathway in which serial propeptide processing normally occurs.
authors.affiliation: University of Leuven, Center for Human Genetics, B-3000 Leuven, Belgium. John.Creemers@med.kuleuven.be
authors.forename: John W M
authors.initials: JW
authors.lastname: Creemers
authors.forename: Yung Seng
authors.initials: YS
authors.lastname: Lee
authors.forename: Robert L
authors.initials: RL
authors.lastname: Oliver
authors.forename: Mithat
authors.initials: M
authors.lastname: Bahceci
authors.forename: Alpaslan
authors.initials: A
authors.lastname: Tuzcu
authors.forename: Deniz
authors.initials: D
authors.lastname: Gokalp
authors.forename: Julia
authors.initials: J
authors.lastname: Keogh
authors.forename: Stefan
authors.initials: S
authors.lastname: Herber
authors.forename: Anne
authors.initials: A
authors.lastname: White
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
authors.forename: I Sadaf
authors.initials: IS
authors.lastname: Farooqi
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D000818:Animals; D001823:Body Composition; D015992:Body Mass Index; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000503:physiopathology*; D005260:Female; D005951:Glucose Tolerance Test; D006801:Humans; D008055:Lipids / Q000502:physiology; D008297:Male; D008875:Middle Aged; D023421:Models, Animal; D018482:Muscle, Skeletal / Q000503:physiopathology*; D009154:Mutation; D009765:Obesity / Q000150:complications / Q000235:genetics* / Q000503:physiopathology; D010809:Physical Fitness; D010957:Plasmids; D011333:Pro-Opiomelanocortin / Q000097:blood / Q000235:genetics* / Q000502:physiology; D012333:RNA, Messenger / Q000235:genetics*
chemical_list: D008055:Lipids; D012333:RNA, Messenger; D011333:Pro-Opiomelanocortin