A novel melanocortin-4 receptor mutation MC4R-P272L associated with severe obesity has increased propensity to be ubiquitinated in the ER in the face of correct folding
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- dc.contributor.author Pérez Jurado, Luis Albertoca
- dc.contributor.author Granell, Susanaca
- dc.contributor.author Serra Juhé, Clara, 1984-ca
- dc.contributor.author Martos Moreno, Gabriel A.ca
- dc.contributor.author Díaz, Franciscaca
- dc.contributor.author Baldini, Giuliaca
- dc.contributor.author Argente, Jesúsca
- dc.date.accessioned 2015-05-13T08:08:06Z
- dc.date.available 2015-05-13T08:08:06Z
- dc.date.issued 2012ca
- dc.description.abstract Heterozygous mutations in the melanocortin-4 receptor (MC4R) gene represent the most frequent cause of monogenic obesity in humans. MC4R mutation analysis in a cohort of 77 children with morbid obesity identified previously unreported heterozygous mutations (P272L, N74I) in two patients inherited from their obese mothers. A rare polymorphism (I251L, allelic frequency: 1/100) reported to protect against obesity was found in another obese patient. When expressed in neuronal cells, the cell surface abundance of wild-type MC4R and of the N74I and I251L variants and the cAMP generated by these receptors in response to exposure to the agonist, α-MSH, were not different. Conversely, MC4R P272L was retained in the endoplasmic reticulum and had reduced cell surface expression and signaling (by ≈3-fold). The chemical chaperone PBA, which promotes protein folding of wild-type MC4R, had minimal effects on the distribution and signaling of the P272L variant. In contrast, incubation with UBE-41, a specific inhibitor of ubiquitin activating enzyme E1, inhibited ubiquitination of MC4R P272L and increased its cell surface expression and signaling to similar levels as wild-type MC4R. UBE41 had much less profound effects on MC4R I316S, another obesity-linked MC4R variant trapped in the ER. These data suggest that P272L is retained in the ER by a propensity to be ubiquitinated in the face of correct folding, which is only minimally shared by MC4R I316S. Thus, studies that combine clinical screening of obese patients and investigation of the functional defects of the obesity-linked MC4R variants can identify specific ways to correct these defects and are the first steps towards personalized medicineen
- dc.description.sponsorship This work has been funded by Fondo de Investigación Sanitaria (PI09/91060, PI10/02512, PI01/00747), CIBERobn Instituto de Salud Carlos III (ISCIII), Fundación Mutua Madrileña (AP2561/2008), Fundación Endocrinología y Nutrición, the National Institutes of Health (R01DK080424 to GB), and the Arkansas Tobacco Settlement (to GB). CS-J and GAM-M were recipients of fellowships from ISCIII (FI08/00365 and CM05/00100, respectively).en
- dc.format.mimetype application/pdfca
- dc.identifier.citation Granell S, Serra-Juhé C, Martos-Moreno GA, Díaz F, Pérez-Jurado LA, Baldini G, Argente J. A novel melanocortin-4 receptor mutation MC4R-P272L associated with severe obesity has increased propensity to be ubiquitinated in the ER in the face of correct folding. PLoS ONE. 2012;7(12):e50894. DOI: 10.1371/journal.pone.0050894ca
- dc.identifier.doi http://dx.doi.org/10.1371/journal.pone.0050894
- dc.identifier.issn 1932-6203ca
- dc.identifier.uri http://hdl.handle.net/10230/23564
- dc.language.iso engca
- dc.publisher Public Library of Science (PLoS)ca
- dc.relation.ispartof PLoS ONE. 2012;7(12):e50894
- dc.rights © 2012 Granell et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are crediteden
- dc.rights.accessRights info:eu-repo/semantics/openAccessca
- dc.subject.other Ubiqüitinaca
- dc.subject.other ADN -- Anàlisica
- dc.title A novel melanocortin-4 receptor mutation MC4R-P272L associated with severe obesity has increased propensity to be ubiquitinated in the ER in the face of correct foldingen
- dc.type info:eu-repo/semantics/articleca
- dc.type.version info:eu-repo/semantics/publishedVersionca