Please use this identifier to cite or link to this item: https://scholarhub.balamand.edu.lb/handle/uob/5260
Title: Mutations and variants of ONECUT1 in diabetes
Authors: Philippi, Anne
Heller, Sandra
Costa, Ivan G
Senée, Valérie
Breunig, Markus
Li, Zhijian
Kwon, Gino
Russell, Ronan
Illing, Anett
Lin, Qiong
Hohwieler, Meike
Degavre, Anne
Zalloua, Pierre
Liebau, Stefan
Schuster, Michael
Krumm, Johannes
Zhang, Xi
Geusz, Ryan
Benthuysen, Jacqueline R
Wang, Allen
Chiou, Joshua
Gaulton, Kyle
Neubauer, Heike
Simon, Eric
Klein, Thomas
Wagner, Martin
Nair, Gopika
Besse, Céline
Dandine-Roulland, Claire
Olaso, Robert
Deleuze, Jean-François
Kuster, Bernhard
Hebrok, Matthias
Seufferlein, Thomas
Sander, Maike
Boehm, Bernhard O
Oswald, Franz
Nicolino, Marc
Julier, Cécile
Kleger, Alexander
Affiliations: Faculty of Medicine 
Keywords: Disease genetics
Embryonic stem cells
Type 2 diabetes
Issue Date: 2021
Part of: Nature Medicine
Volume: 27
Start page: 1928
End page: 1940
Abstract: 
Genes involved in distinct diabetes types suggest shared disease mechanisms. Here we show that One Cut Homeobox 1 (ONECUT1) mutations cause monogenic recessive syndromic diabetes in two unrelated patients, characterized by intrauterine growth retardation, pancreas hypoplasia and gallbladder agenesis/hypoplasia, and early-onset diabetes in heterozygous relatives. Heterozygous carriers of rare coding variants of ONECUT1 define a distinctive subgroup of diabetic patients with early-onset, nonautoimmune diabetes, who respond well to diabetes treatment. In addition, common regulatory ONECUT1 variants are associated with multifactorial type 2 diabetes. Directed differentiation of human pluripotent stem cells revealed that loss of ONECUT1 impairs pancreatic progenitor formation and a subsequent endocrine program. Loss of ONECUT1 altered transcription factor binding and enhancer activity and NKX2.2/NKX6.1 expression in pancreatic progenitor cells. Collectively, we demonstrate that ONECUT1 controls a transcriptional and epigenetic machinery regulating endocrine development, involved in a spectrum of diabetes, encompassing monogenic (recessive and dominant) as well as multifactorial inheritance. Our findings highlight the broad contribution of ONECUT1 in diabetes pathogenesis, marking an important step toward precision diabetes medicine.
URI: https://scholarhub.balamand.edu.lb/handle/uob/5260
ISSN: 10788956
DOI: 10.1038/s41591-021-01502-7
Open URL: Link to full text
Type: Journal Article
Appears in Collections:Faculty of Medicine

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