Çiğdem Köroğlu, Michael Traurig, Yunhua L. Muller, Samantha E. Day, Paolo Piaggi, Kim Wiedrich, Laura Vazquez, Robert L. Hanson, Cristopher V. Van Hout, Anna Alkelai, Alan R. Shuldiner, Clifton Bogardus, Leslie J. Baier
{"title":"单基因肥胖症相关基因中罕见编码变异的鉴定和功能验证。","authors":"Çiğdem Köroğlu, Michael Traurig, Yunhua L. Muller, Samantha E. Day, Paolo Piaggi, Kim Wiedrich, Laura Vazquez, Robert L. Hanson, Cristopher V. Van Hout, Anna Alkelai, Alan R. Shuldiner, Clifton Bogardus, Leslie J. Baier","doi":"10.1002/oby.24101","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Objective</h3>\n \n <p>Rare cases of monogenic obesity, which may respond to specific therapeutics, can remain undetected in populations in which polygenic obesity is prevalent. This study examined rare DNA variation in established monogenic obesity genes within a community using whole-exome sequence data from 6803 longitudinally studied individuals.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>Exome data across 15 monogenic obesity genes were analyzed for nonsynonymous variants observed in any child with a maximum BMI <i>z</i> score > 2 (<i>N</i> = 279) but not observed in a child with a maximum BMI <i>z</i> score ≤ 0 (<i>n</i> = 1542) or that occurred in adults in the top 5th percentile of BMI (<i>n</i> = 263) but not in adults below the median BMI (<i>n</i> = 2629). Variants were then functionally analyzed using luciferase assays.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>The comparisons between cases of obesity and controls identified eight missense variants in six genes: <i>DYRK1B</i>, <i>KSR2</i>, <i>MC4R</i>, <i>NTRK2</i>, <i>PCSK1</i>, and <i>SIM1</i>. Among these, <i>MC4R</i> p.A303P and p.R165G were previously shown to impair MC4R function. Functional analyses of the remaining six variants suggest that <i>KSR2</i> p.I402F and p.T193I and <i>NTRK2</i> p.S249Y alter protein function.</p>\n </section>\n \n <section>\n \n <h3> Conclusions</h3>\n \n <p>In addition to <i>MC4R</i>, rare missense variants in <i>KSR2</i> and <i>NTRK2</i> may potentially explain the severe obesity observed for the carriers.</p>\n </section>\n </div>","PeriodicalId":215,"journal":{"name":"Obesity","volume":"32 9","pages":"1769-1777"},"PeriodicalIF":4.2000,"publicationDate":"2024-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/oby.24101","citationCount":"0","resultStr":"{\"title\":\"Identification and functional validation of rare coding variants in genes linked to monogenic obesity\",\"authors\":\"Çiğdem Köroğlu, Michael Traurig, Yunhua L. Muller, Samantha E. Day, Paolo Piaggi, Kim Wiedrich, Laura Vazquez, Robert L. Hanson, Cristopher V. Van Hout, Anna Alkelai, Alan R. Shuldiner, Clifton Bogardus, Leslie J. Baier\",\"doi\":\"10.1002/oby.24101\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Objective</h3>\\n \\n <p>Rare cases of monogenic obesity, which may respond to specific therapeutics, can remain undetected in populations in which polygenic obesity is prevalent. This study examined rare DNA variation in established monogenic obesity genes within a community using whole-exome sequence data from 6803 longitudinally studied individuals.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods</h3>\\n \\n <p>Exome data across 15 monogenic obesity genes were analyzed for nonsynonymous variants observed in any child with a maximum BMI <i>z</i> score > 2 (<i>N</i> = 279) but not observed in a child with a maximum BMI <i>z</i> score ≤ 0 (<i>n</i> = 1542) or that occurred in adults in the top 5th percentile of BMI (<i>n</i> = 263) but not in adults below the median BMI (<i>n</i> = 2629). Variants were then functionally analyzed using luciferase assays.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>The comparisons between cases of obesity and controls identified eight missense variants in six genes: <i>DYRK1B</i>, <i>KSR2</i>, <i>MC4R</i>, <i>NTRK2</i>, <i>PCSK1</i>, and <i>SIM1</i>. Among these, <i>MC4R</i> p.A303P and p.R165G were previously shown to impair MC4R function. Functional analyses of the remaining six variants suggest that <i>KSR2</i> p.I402F and p.T193I and <i>NTRK2</i> p.S249Y alter protein function.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Conclusions</h3>\\n \\n <p>In addition to <i>MC4R</i>, rare missense variants in <i>KSR2</i> and <i>NTRK2</i> may potentially explain the severe obesity observed for the carriers.</p>\\n </section>\\n </div>\",\"PeriodicalId\":215,\"journal\":{\"name\":\"Obesity\",\"volume\":\"32 9\",\"pages\":\"1769-1777\"},\"PeriodicalIF\":4.2000,\"publicationDate\":\"2024-08-28\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://onlinelibrary.wiley.com/doi/epdf/10.1002/oby.24101\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Obesity\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://onlinelibrary.wiley.com/doi/10.1002/oby.24101\",\"RegionNum\":2,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"ENDOCRINOLOGY & METABOLISM\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Obesity","FirstCategoryId":"3","ListUrlMain":"https://onlinelibrary.wiley.com/doi/10.1002/oby.24101","RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"ENDOCRINOLOGY & METABOLISM","Score":null,"Total":0}
Identification and functional validation of rare coding variants in genes linked to monogenic obesity
Objective
Rare cases of monogenic obesity, which may respond to specific therapeutics, can remain undetected in populations in which polygenic obesity is prevalent. This study examined rare DNA variation in established monogenic obesity genes within a community using whole-exome sequence data from 6803 longitudinally studied individuals.
Methods
Exome data across 15 monogenic obesity genes were analyzed for nonsynonymous variants observed in any child with a maximum BMI z score > 2 (N = 279) but not observed in a child with a maximum BMI z score ≤ 0 (n = 1542) or that occurred in adults in the top 5th percentile of BMI (n = 263) but not in adults below the median BMI (n = 2629). Variants were then functionally analyzed using luciferase assays.
Results
The comparisons between cases of obesity and controls identified eight missense variants in six genes: DYRK1B, KSR2, MC4R, NTRK2, PCSK1, and SIM1. Among these, MC4R p.A303P and p.R165G were previously shown to impair MC4R function. Functional analyses of the remaining six variants suggest that KSR2 p.I402F and p.T193I and NTRK2 p.S249Y alter protein function.
Conclusions
In addition to MC4R, rare missense variants in KSR2 and NTRK2 may potentially explain the severe obesity observed for the carriers.
期刊介绍：
Obesity is the official journal of The Obesity Society and is the premier source of information for increasing knowledge, fostering translational research from basic to population science, and promoting better treatment for people with obesity. Obesity publishes important peer-reviewed research and cutting-edge reviews, commentaries, and public health and medical developments.
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