Identification of p.Met215Ile mutation of the <i>MC4R</i> gene in a Moroccan woman with obesity

Fessikh, Meriem El; Belghiti, Hakim; Elkarhat, Zouhair; Guerinech, Hassania; Dakka, Nadia; El-Baghdadi, Jamila

doi:10.1002/ccr3.5059

Clinical Case Reports

2021

DOI: 10.1002/ccr3.5059

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Identification of p.Met215Ile mutation of the MC4R gene in a Moroccan woman with obesity

Meriem El Fessikh

Hakim Belghiti²,

Zouhair Elkarhat

et al.

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmerc ial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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2024

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References 39 publications

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MC4R Variants Modulate α-MSH and Setmelanotide Induced Cellular Signaling at Multiple Levels

Rodríguez Rondón,

Welling,

van den Akker

et al. 2024

The Journal of Clinical Endocrinology &Amp; Metabolism

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Context Melanocortin-4 receptor (MC4R) plays an important role in body weight regulation. Pathogenic MC4R variants are the most common cause of monogenic obesity. Objective We have identified 17 MC4R variants in adult and pediatric patients with obesity. Here, we aimed to functionally characterize these variants by analyzing four different aspects of MC4R signaling. In addition, we aimed to analyze the effect of setmelanotide, a potent MC4R agonist, on these MC4R variants. Materials and Methods Cell surface expression and α-MSH- or setmelanotide-induced cAMP response, β-arrestin-2 recruitment, and ERK activation were measured in cells expressing either wild type (WT) or variant MC4R. Results We found a large heterogeneity in the function of these variants. We identified variants with a loss of response for all studied MC4R signaling, variants with no cAMP accumulation or ERK activation but normal β-arrestin-2 recruitment, and variants with normal cAMP accumulation and ERK activation but decreased β-arrestin-2 recruitment, indicating disrupted desensitization and signaling mechanisms. Setmelanotide displayed a greater potency and similar efficacy as α-MSH, and induced significantly increased maximal cAMP responses of several variants compared to α-MSH. Despite the heterogeneity in functional response, there was no apparent difference in the obesity phenotype in our patients. Discussion We show that these obesity-associated MC4R variants affect MC4R signaling differently, yet leading to a comparable clinical phenotype. Our results demonstrate the clinical importance of assessing the effect of MC4R variants on a range of molecular signaling mechanisms to determine their association with obesity, which may aid in improving personalized treatment.

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MC4R Variants Modulate α-MSH and Setmelanotide Induced Cellular Signaling at Multiple Levels

Rodríguez Rondón,

Welling,

van den Akker

et al. 2024

The Journal of Clinical Endocrinology &Amp; Metabolism

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Identification of p.Met215Ile mutation of the MC4R gene in a Moroccan woman with obesity

Abstract: This is an open access article under the terms of the Creat ive Commo ns Attri butio n-NonCo mmerc ial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

Cited by 1 publication

References 39 publications

MC4R Variants Modulate α-MSH and Setmelanotide Induced Cellular Signaling at Multiple Levels

MC4R Variants Modulate α-MSH and Setmelanotide Induced Cellular Signaling at Multiple Levels

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