Mutations in the amino-terminal region of proopiomelanocortin (POMC) in patients with early-onset obesity impair POMC sorting to the regulated secretory pathway

John W M Creemers, Seng Lee Yung, Robert L. Oliver, Mithat Bahceci, Alpaslan Tuzcu, Deniz Gokalp, Julia Keogh, Stefan Herber, Anne White, Stephen O'Rahilly, I. Sadaf Farooqi

    Research output: Contribution to journalArticlepeer-review

    Abstract

    Context: 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. Design and Patients: 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 β-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. Conclusion: 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. Copyright © 2008 by The Endocrine Society.
    Original languageEnglish
    Pages (from-to)4494-4499
    Number of pages5
    JournalJournal of Clinical Endocrinology and Metabolism
    Volume93
    Issue number11
    DOIs
    Publication statusPublished - Nov 2008

    Keywords

    • metabolism: Adipocytes
    • Animals
    • Body Composition
    • Body Mass Index
    • Case-Control Studies
    • Cross-Sectional Studies
    • complications: Diabetes Mellitus, Type 2
    • Female
    • Glucose Tolerance Test
    • Humans
    • physiology: Lipids
    • Male
    • Middle Aged
    • Models, Animal
    • physiopathology: Muscle, Skeletal
    • Mutation
    • complications: Obesity
    • Physical Fitness
    • Plasmids
    • blood: Pro-Opiomelanocortin
    • genetics: RNA, Messenger

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