{"title":"遗传和表观遗传 GNAS 改变在早发性肥胖症发病过程中的作用","authors":"Alaa Abbas , Ayat S Hammad , Mashael Al-Shafai","doi":"10.1016/j.mrrev.2023.108487","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><p><em>GNAS</em> (guanine nucleotide-binding protein, alpha stimulating) is an imprinted gene that encodes G<sub>s</sub>α, the α subunit of the heterotrimeric stimulatory G protein. This subunit mediates the signalling of a diverse array of G protein-coupled receptors (GPCRs), including the melanocortin 4 receptor (MC4R) that serves a pivotal role in regulating food intake, energy homoeostasis, and body weight. Genetic or epigenetic alterations in <em>GNAS</em> are known to cause pseudohypoparathyroidism in its different subtypes and have been recently associated with isolated, early-onset, severe obesity. Given the diverse biological functions that G<sub>s</sub>α serves, multiple molecular mechanisms involving various GPCRs, such as MC4R, β<sub>2</sub>- and β<sub>3</sub>-adrenoceptors, and corticotropin-releasing hormone receptor, have been implicated in the pathophysiology of severe, early-onset obesity that results from genetic or epigenetic <em>GNAS</em> changes.</p></div><div><h3>Scope of review</h3><p>This review examines the structure and function of <em>GNAS</em> and provides an overview of the disorders that are caused by defects in this gene and may feature early-onset obesity. Moreover, it elucidates the potential molecular mechanisms underlying G<sub>s</sub>α deficiency-induced early-onset obesity, highlighting some of their implications for the diagnosis, management, and treatment of this complex condition.</p></div><div><h3>Major conclusions</h3><p>G<sub>s</sub>α deficiency is an underappreciated cause of early-onset, severe obesity. Therefore, screening children with unexplained, severe obesity for <em>GNAS</em> defects is recommended, to enhance the molecular diagnosis and management of this condition.</p></div>","PeriodicalId":49789,"journal":{"name":"Mutation Research-Reviews in Mutation Research","volume":null,"pages":null},"PeriodicalIF":6.4000,"publicationDate":"2023-12-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1383574223000352/pdfft?md5=090d4b148a016ca8a32bd7dec45a574d&pid=1-s2.0-S1383574223000352-main.pdf","citationCount":"0","resultStr":"{\"title\":\"The role of genetic and epigenetic GNAS alterations in the development of early-onset obesity\",\"authors\":\"Alaa Abbas , Ayat S Hammad , Mashael Al-Shafai\",\"doi\":\"10.1016/j.mrrev.2023.108487\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background</h3><p><em>GNAS</em> (guanine nucleotide-binding protein, alpha stimulating) is an imprinted gene that encodes G<sub>s</sub>α, the α subunit of the heterotrimeric stimulatory G protein. This subunit mediates the signalling of a diverse array of G protein-coupled receptors (GPCRs), including the melanocortin 4 receptor (MC4R) that serves a pivotal role in regulating food intake, energy homoeostasis, and body weight. Genetic or epigenetic alterations in <em>GNAS</em> are known to cause pseudohypoparathyroidism in its different subtypes and have been recently associated with isolated, early-onset, severe obesity. Given the diverse biological functions that G<sub>s</sub>α serves, multiple molecular mechanisms involving various GPCRs, such as MC4R, β<sub>2</sub>- and β<sub>3</sub>-adrenoceptors, and corticotropin-releasing hormone receptor, have been implicated in the pathophysiology of severe, early-onset obesity that results from genetic or epigenetic <em>GNAS</em> changes.</p></div><div><h3>Scope of review</h3><p>This review examines the structure and function of <em>GNAS</em> and provides an overview of the disorders that are caused by defects in this gene and may feature early-onset obesity. Moreover, it elucidates the potential molecular mechanisms underlying G<sub>s</sub>α deficiency-induced early-onset obesity, highlighting some of their implications for the diagnosis, management, and treatment of this complex condition.</p></div><div><h3>Major conclusions</h3><p>G<sub>s</sub>α deficiency is an underappreciated cause of early-onset, severe obesity. Therefore, screening children with unexplained, severe obesity for <em>GNAS</em> defects is recommended, to enhance the molecular diagnosis and management of this condition.</p></div>\",\"PeriodicalId\":49789,\"journal\":{\"name\":\"Mutation Research-Reviews in Mutation Research\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":6.4000,\"publicationDate\":\"2023-12-14\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.sciencedirect.com/science/article/pii/S1383574223000352/pdfft?md5=090d4b148a016ca8a32bd7dec45a574d&pid=1-s2.0-S1383574223000352-main.pdf\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Mutation Research-Reviews in Mutation Research\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S1383574223000352\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOTECHNOLOGY & APPLIED MICROBIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Mutation Research-Reviews in Mutation Research","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1383574223000352","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOTECHNOLOGY & APPLIED MICROBIOLOGY","Score":null,"Total":0}
The role of genetic and epigenetic GNAS alterations in the development of early-onset obesity
Background
GNAS (guanine nucleotide-binding protein, alpha stimulating) is an imprinted gene that encodes Gsα, the α subunit of the heterotrimeric stimulatory G protein. This subunit mediates the signalling of a diverse array of G protein-coupled receptors (GPCRs), including the melanocortin 4 receptor (MC4R) that serves a pivotal role in regulating food intake, energy homoeostasis, and body weight. Genetic or epigenetic alterations in GNAS are known to cause pseudohypoparathyroidism in its different subtypes and have been recently associated with isolated, early-onset, severe obesity. Given the diverse biological functions that Gsα serves, multiple molecular mechanisms involving various GPCRs, such as MC4R, β2- and β3-adrenoceptors, and corticotropin-releasing hormone receptor, have been implicated in the pathophysiology of severe, early-onset obesity that results from genetic or epigenetic GNAS changes.
Scope of review
This review examines the structure and function of GNAS and provides an overview of the disorders that are caused by defects in this gene and may feature early-onset obesity. Moreover, it elucidates the potential molecular mechanisms underlying Gsα deficiency-induced early-onset obesity, highlighting some of their implications for the diagnosis, management, and treatment of this complex condition.
Major conclusions
Gsα deficiency is an underappreciated cause of early-onset, severe obesity. Therefore, screening children with unexplained, severe obesity for GNAS defects is recommended, to enhance the molecular diagnosis and management of this condition.
期刊介绍:
The subject areas of Reviews in Mutation Research encompass the entire spectrum of the science of mutation research and its applications, with particular emphasis on the relationship between mutation and disease. Thus this section will cover advances in human genome research (including evolving technologies for mutation detection and functional genomics) with applications in clinical genetics, gene therapy and health risk assessment for environmental agents of concern.