Mutations in the Amino-Terminal Region of Proopiomelanocortin (POMC) in Patients with Early-Onset Obesity Impair POMC Sorting to the Regulated Secretory Pathway

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dc.contributor.authorCreemers, John W. M.
dc.contributor.authorLee, Yung Seng
dc.contributor.authorOliver, Robert L.
dc.contributor.authorBahceci, Mithat
dc.contributor.authorTuzcu, Alpaslan
dc.contributor.authorGokalp, Deniz
dc.contributor.authorKeogh, Julia
dc.date.accessioned2024-04-24T17:15:01Z
dc.date.available2024-04-24T17:15:01Z
dc.date.issued2008
dc.departmentDicle Üniversitesien_US
dc.description.abstractContext: 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 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. 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. (J Clin Endocrinol Metab 93: 4494-4499, 2008)en_US
dc.description.sponsorshipNational Institute for Health Research Cambridge Biomedical Research Centre; Medical Research Council and Diabesity [EU FP6 LSHM-CT-2003-503041]; Wellcome Trust; Geconcerteerde onderzoeksactie van de Vlaamse gemeenschap [2008/16]; Agency for Science, Technology, and Research, Singapore; MRC [G9824984] Funding Source: UKRI; Medical Research Council [G9824984] Funding Source: researchfishen_US
dc.description.sponsorshipThis study was supported by the National Institute for Health Research Cambridge Biomedical Research Centre, Medical Research Council and Diabesity (EU FP6 LSHM-CT-2003-503041) (S.O.R.), the Wellcome Trust (I.S.F.and A.W.), and Geconcerteerde onderzoeksactie van de Vlaamse gemeenschap 2008/16 (J.C.).Y.S.L.was supported by an international fellowship from the Agency for Science, Technology, and Research, Singapore.en_US
dc.identifier.doi10.1210/jc.2008-0954
dc.identifier.endpage4499en_US
dc.identifier.issn0021-972X
dc.identifier.issue11en_US
dc.identifier.pmid18697863en_US
dc.identifier.scopus2-s2.0-84992268836en_US
dc.identifier.scopusqualityN/Aen_US
dc.identifier.startpage4494en_US
dc.identifier.urihttps://doi.org/10.1210/jc.2008-0954
dc.identifier.urihttps://hdl.handle.net/11468/18305
dc.identifier.volume93en_US
dc.identifier.wosWOS:000260661900047
dc.identifier.wosqualityQ1
dc.indekslendigikaynakWeb of Science
dc.indekslendigikaynakScopus
dc.indekslendigikaynakPubMed
dc.language.isoenen_US
dc.publisherEndocrine Socen_US
dc.relation.ispartofJournal of Clinical Endocrinology & Metabolismen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subject[No Keyword]en_US
dc.titleMutations in the Amino-Terminal Region of Proopiomelanocortin (POMC) in Patients with Early-Onset Obesity Impair POMC Sorting to the Regulated Secretory Pathwayen_US
dc.typeArticleen_US

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