Rescue of defective MC4R cell-surface expression and signaling by a novel pharmacoperone Ipsen 17

Wang, Xiaohua; Wang, Haomeng; Zhao, Baolei; Yu, Peng; Fan, Zhen‐Chuan

doi:10.1530/jme-14-0005

Cited by 26 publications

(12 citation statements)

References 49 publications

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“…In addition to these novel variants, previously described mutations in MC4R were found in four patients (p.R165W, c.493C>T in exon 1 in three of four, and p.V166I, c.496G>A in exon 1 in one) (15,16).…”

Section: Resultsmentioning

confidence: 82%

Novel Mutations in Obesity-related Genes in Turkish Children with Non-syndromic Early Onset Severe Obesity: A Multicentre Study

Akıncı

Türkkahraman

Tekedereli

et al. 2019

Jcrpe

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Objective:Non syndromic monogenic obesity is a rare cause of early onset severe obesity in the childhood period. This form may not be distinguishable from other forms of severe obesity without genetic analysis, particularly if patients do not exibit any physical abnormalities or developmental delay. The aim of this study was to screen 41 different obesity-related genes in children with non-syndromic early onset severe obesity.Methods:Children with severe (body mass index-standard deviation score >3) and early onset (<7 years) obesity were screened by next-generation sequencing based, targeted DNA custom panel for 41 known-obesity-related genes and the results were confirmed by Sanger technique.Results:Six novel variants were identified in five candidate genes in seven out of 105 children with severe obesity; two in SIM1 (p.W306C and p.Q36X), one in POMC (p.Y160H), one in PCSK1 (p.W130G fs Ter8), two in MC4R (p.D126E) and one in LEPR (p.Q4H). Additionally, two previously known variations in MC4R were identified in four patients (p.R165W in three, and p.V166I in one).Conclusion:We identified six novel and four previously described variants in six obesity-related genes in 11 out of 105 childrens with early onset severe obesity. The prevalence of monogenic obesity was 10.4% in our cohort.

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Section: Resultsmentioning

confidence: 82%

Novel Mutations in Obesity-related Genes in Turkish Children with Non-syndromic Early Onset Severe Obesity: A Multicentre Study

Akıncı

Türkkahraman

Tekedereli

et al. 2019

Jcrpe

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“… 26 , 94 , 95 Recently, new MC4R antagonists, Ipsen 5i and Ipsen 17, were identified, which rescue a broader spectrum of MC4R mutants with a high efficiency at concentrations as low as 10 −9 and 10 −8 M, respectively. 96 , 97 Functionality was restored in most of the studied cases. As expected, these chaperones were unable to functionally rescue mutants with additional defects, such as impaired ligand binding ability.…”

Section: Mutations Affecting Gpcr Signalingmentioning

confidence: 73%

How genetic errors in GPCRs affect their function: Possible therapeutic strategies

Stoy

Gurevich

2015

Genes & Diseases

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Activating and inactivating mutations in numerous human G protein-coupled receptors (GPCRs) are associated with a wide range of disease phenotypes. Here we use several class A GPCRs with a particularly large set of identified disease-associated mutations, many of which were biochemically characterized, along with known GPCR structures and current models of GPCR activation, to understand the molecular mechanisms yielding pathological phenotypes. Based on this mechanistic understanding we also propose different therapeutic approaches, both conventional, using small molecule ligands, and novel, involving gene therapy.

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“…Using pharmacological chaperones for MC4R represents a possibility for the development of a targeted treatment of severe early-onset obesity caused by MC4R mutations. A study demonstrated that a novel human MC4R antagonist, Ipsen 17, serving as a pharmacological chaperone of human MC4R, increased the cell surface expression of MC4R mutants and their signaling capacity upon α-MSH stimulation [ 74 ]. Thus, using pharmacological chaperones against MC4R mutants provides an exciting disease-modifying opportunity for severe early-onset morbid obesity.…”

Section: Perspectivesmentioning

confidence: 99%

Rare Genetic Forms of Obesity: Clinical Approach and Current Treatments in 2016

Huvenne

Dubern²,

Clément³

et al. 2016

Obes Facts

190

191

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Obesity results from a synergistic relationship between genes and the environment. The phenotypic expression of genetic factors involved in obesity is variable, allowing to distinguish several clinical pictures of obesity. Monogenic obesity is described as rare and severe early-onset obesity with abnormal feeding behavior and endocrine disorders. This is mainly due to autosomal recessive mutations in genes of the leptin-melanocortin pathway which plays a key role in the hypothalamic control of food intake. Melanocortin 4 receptor(MC4R)-linked obesity is characterized by the variable severity of obesity and no notable additional phenotypes. Mutations in the MC4R gene are involved in 2-3% of obese children and adults; the majority of these are heterozygous. Syndromic obesity is associated with mental retardation, dysmorphic features, and organ-specific developmental abnormalities. Additional genes participating in the development of hypothalamus and central nervous system have been regularly identified. But to date, not all involved genes have been identified so far. New diagnostic tools, such as whole-exome sequencing, will probably help to identify other genes. Managing these patients is challenging. Indeed, specific treatments are available only for specific types of monogenic obesity, such as leptin deficiency. Data on bariatric surgery are limited and controversial. New molecules acting on the leptin-melanocortin pathway are currently being developed.

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Rescue of defective MC4R cell-surface expression and signaling by a novel pharmacoperone Ipsen 17

Cited by 26 publications

References 49 publications

Novel Mutations in Obesity-related Genes in Turkish Children with Non-syndromic Early Onset Severe Obesity: A Multicentre Study

Novel Mutations in Obesity-related Genes in Turkish Children with Non-syndromic Early Onset Severe Obesity: A Multicentre Study

How genetic errors in GPCRs affect their function: Possible therapeutic strategies

Rare Genetic Forms of Obesity: Clinical Approach and Current Treatments in 2016

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