Mutations in the Amino-Terminal Region of Proopiomelanocortin (POMC) in Patients with Early-Onset Obesity Impair POMC Sorting to the Regulated Secretory Pathway
| Autor: | Yung Seng Lee, Alpaslan Tuzcu, Mithat Bahceci, Stephen O'Rahilly, Deniz Gokalp, Anne White, Robert L. Oliver, I. Sadaf Farooqi, John W.M. Creemers, Julia M. Keogh, Stefan Herber |
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| Rok vydání: | 2008 |
| Předmět: |
Male
endocrine system medicine.medical_specialty Pro-Opiomelanocortin Endocrinology Diabetes and Metabolism Clinical Biochemistry Prohormone Mutant Context (language use) medicine.disease_cause Biochemistry Body Mass Index Endocrinology Proopiomelanocortin Internal medicine Adipocytes medicine Animals Humans Missense mutation Obesity RNA Messenger Muscle Skeletal Gene Mutation biology digestive oral and skin physiology Biochemistry (medical) Transfection Glucose Tolerance Test Middle Aged Lipids Cross-Sectional Studies Diabetes Mellitus Type 2 nervous system Physical Fitness Case-Control Studies Models Animal Body Composition biology.protein Female hormones hormone substitutes and hormone antagonists Plasmids medicine.drug |
| Zdroj: | The Journal of Clinical Endocrinology & Metabolism. 93:4494-4499 |
| ISSN: | 1945-7197 0021-972X |
| DOI: | 10.1210/jc.2008-0954 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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