title: Hyperphagia and early-onset obesity due to a novel homozygous missense mutation in prohormone convertase 1/3.
abstract: BACKGROUND
  Congenital deficiency of the neuroendocrine-specific enzyme prohormone convertase (PC) 1/3 leads to a syndrome characterized by obesity, small intestinal dysfunction, and dysregulation of glucose homeostasis in humans. To date, only two unrelated subjects with this disorder have been reported.
  
  
  METHODS
  We now report a third proband, a 6-yr-old boy, offspring of a consanguineous union of parents of North African origin, who was homozygous for a novel missense mutation Ser307Leu. We characterized the functional properties of the mutant PC1/3 and characterized the clinical phenotype of the patient.
  
  
  RESULTS
  In vitro this mutation markedly impairs the catalytic activity of the convertase. However, in contrast to other previously described naturally occurring mutations, intracellular trafficking of this mutant enzyme appeared normal. The Ser307Leu mutant retained some autocatalytic activity, even though it was completely inactive on other substrates. As with the previous two patients, this child had obesity and persistent diarrhea, however, there was no history of reactive hypoglycemia. The patient showed markedly increased food intake at an ad libitum test meal, confirming that hyperphagia makes a major contribution to the obesity seen in this syndrome.
  
  
  CONCLUSIONS
  This case extends the clinical and molecular spectrum of human congenital PC1/3 deficiency.
authors.affiliation: University Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge CB2 2XY, United Kingdom.
authors.forename: I Sadaf
authors.initials: IS
authors.lastname: Farooqi
authors.forename: Karolien
authors.initials: K
authors.lastname: Volders
authors.forename: Richard
authors.initials: R
authors.lastname: Stanhope
authors.forename: Robert
authors.initials: R
authors.lastname: Heuschkel
authors.forename: Anne
authors.initials: A
authors.lastname: White
authors.forename: Emma
authors.initials: E
authors.lastname: Lank
authors.forename: Julia
authors.initials: J
authors.lastname: Keogh
authors.forename: Stephen
authors.initials: S
authors.lastname: O'Rahilly
authors.forename: John W M
authors.initials: JW
authors.lastname: Creemers
mesh_terms: D017668:Age of Onset; D002478:Cells, Cultured; D002648:Child; D006720:Homozygote; D006801:Humans; D006963:Hyperphagia / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense; D009765:Obesity / Q000235:genetics*; D045664:Proprotein Convertase 1 / Q000235:genetics*; D014162:Transfection
chemical_list: D045664:Proprotein Convertase 1