Sarah Merz, Valerie Senee, Anne Philippi, Franz Oswald, Mina Shaigan, Marita Fuehrer, Cosima Drewes, Chantal Allgoewer, Rupert Oellinger, Martin Heni, Anne Boland, Jean-Francois Deleuze, Franziska Birkhofer, Eduardo G Gusmao, Martin Wagner, Meike Hohwieler, Markus Breunig, Roland Rad, Reiner Siebert, David Alexander Christian Messerer, Ivan Gesteira Costa Filho, Fernando Alvarez, Cecile Julier, Sandra Heller, Alexander Kleger
{"title":"A ONECUT1 regulatory, non-coding region in pancreatic development and diabetes","authors":"Sarah Merz, Valerie Senee, Anne Philippi, Franz Oswald, Mina Shaigan, Marita Fuehrer, Cosima Drewes, Chantal Allgoewer, Rupert Oellinger, Martin Heni, Anne Boland, Jean-Francois Deleuze, Franziska Birkhofer, Eduardo G Gusmao, Martin Wagner, Meike Hohwieler, Markus Breunig, Roland Rad, Reiner Siebert, David Alexander Christian Messerer, Ivan Gesteira Costa Filho, Fernando Alvarez, Cecile Julier, Sandra Heller, Alexander Kleger","doi":"10.1101/2024.07.23.24310605","DOIUrl":null,"url":null,"abstract":"In a patient with permanent neonatal syndromic diabetes clinically similar to cases with ONECUT1 biallelic mutations, we identified a disease-causing deletion located upstream of ONECUT1. Through genetic, genomic and functional studies we identified a crucial regulatory region acting as an enhancer of ONECUT1 specifically during pancreatic development. This enhancer region contains a low-frequency variant showing strong association with type 2 diabetes and other glycemic traits, thus extending the contribution of this region to common forms of diabetes. Clinical relevance is provided by experimentally tailored therapy options for patients carrying ONECUT1 coding or regulatory mutations.","PeriodicalId":501419,"journal":{"name":"medRxiv - Endocrinology","volume":"41 1","pages":""},"PeriodicalIF":0.0000,"publicationDate":"2024-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"medRxiv - Endocrinology","FirstCategoryId":"1085","ListUrlMain":"https://doi.org/10.1101/2024.07.23.24310605","RegionNum":0,"RegionCategory":null,"ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"","JCRName":"","Score":null,"Total":0}
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Abstract
In a patient with permanent neonatal syndromic diabetes clinically similar to cases with ONECUT1 biallelic mutations, we identified a disease-causing deletion located upstream of ONECUT1. Through genetic, genomic and functional studies we identified a crucial regulatory region acting as an enhancer of ONECUT1 specifically during pancreatic development. This enhancer region contains a low-frequency variant showing strong association with type 2 diabetes and other glycemic traits, thus extending the contribution of this region to common forms of diabetes. Clinical relevance is provided by experimentally tailored therapy options for patients carrying ONECUT1 coding or regulatory mutations.
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