This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Creemers, J. W. M. Articles by Farooqi, I. S. Search for Related Content PubMed PubMed Citation Articles by Creemers, J. W. M. Articles by Farooqi, I. S. Related Collections Neuroendocrinology and Pituitary Obesity

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

University of Leuven (J.W.M.C.), Center for Human Genetics, B-3000 Leuven, Belgium; University of Cambridge (Y.S.L., J.K., S.O., I.S.F.), Metabolic Research Laboratories, Institute of Metabolic Science, Addenbrooke’s Hospital, Cambridge CB2 0QQ, United Kingdom; Department of Paediatrics (Y.S.L.), Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117595; University of Manchester (R.L.O., A.W.), Endocrine Sciences Research Group, Faculties of Life Sciences and Medical and Human Sciences, Manchester M13 9PL, United Kingdom; Department of Endocrinology and Metabolism (M.B., A.T., D.G.), Dicle University School of Medicine, 21280 Diyarbakir, Turkey; and Princess of Wales Hospital (S.H.), Grimsby DN33 2BA, United Kingdom

Address all correspondence and requests for reprints to: John W. M. Creemers, University of Leuven, Center for Human Genetics, B-3000 Leuven, Belgium. E-mail: John.Creemers{at}med.kuleuven.be.

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.