德国乌尔姆大学Alexander Kleger、法国巴黎大学Cécile Julier等研究人员合作发现糖尿病中ONECUT1的突变和变体。该项研究成果于2021年10月18日在线发表在《自然—医学》杂志上。

研究人员发现，ONECUT1（One Cut Homeobox 1）突变在两个没有血缘关系的患者中引起单基因隐性综合征糖尿病，其特点是宫内发育迟缓、胰腺发育不良和胆囊缺失/发育不良，以及杂合子亲属的早发糖尿病。ONECUT1罕见编码变体的杂合子携带者定义了一个独特的糖尿病患者亚组，他们具有早发的非自身免疫性糖尿病，对糖尿病治疗反应良好。此外，常见的调节性ONECUT1变体与多因素的2型糖尿病有关。人类多能干细胞的定向分化显示，ONECUT1的缺失会损害胰腺祖细胞的形成和随后的内分泌程序。ONECUT1的缺失改变了转录因子的结合和增强子的活性以及胰腺祖细胞中NKX2.2/NKX6.1的表达。

总的来说，研究人员证明ONECUT1控制着调节内分泌发育的转录和表观遗传机制，这些涉及到糖尿病的一系列问题，包括单基因（隐性和显性）以及多因素的遗传。这项发现突出了ONECUT1在糖尿病发病机制中的广泛贡献，并标志着向精准糖尿病医学迈出的重要一步。

据介绍，涉及不同糖尿病类型的基因提示了共同的疾病机制。

附：英文原文

Title: Mutations and variants of ONECUT1 in diabetes

Author: Philippi, Anne, Heller, Sandra, Costa, Ivan G., Sene, Valrie, 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, Cline, Dandine-Roulland, Claire, Olaso, Robert, Deleuze, Jean-Franois, Kuster, Bernhard, Hebrok, Matthias, Seufferlein, Thomas, Sander, Maike, Boehm, Bernhard O., Oswald, Franz, Nicolino, Marc, Julier, Ccile, Kleger, Alexander

Issue&Volume: 2021-10-18

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. Clinical and genetic phenotyping of consanguineous family cases of neonatal syndromic diabetes and type 2 diabetes, combined with in-depth functional studies in pluripotent stem cells, reveals a role for genetic variants of ONECUT1 in monogenic and multifactorial diabetes.

DOI: 10.1038/s41591-021-01502-7

Source: https://www.nature.com/articles/s41591-021-01502-7