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.

涉及不同糖尿病类型的基因表明了共同的疾病机制。在这里，我们显示 One Cut Homeobox 1 ( ONECUT1 ) 突变导致两名无关患者出现单基因隐性综合征糖尿病，其特征是宫内发育迟缓、胰腺发育不全和胆囊发育不全/发育不全，以及杂合子亲属中的早发性糖尿病。ONECUT1的罕见编码变异的杂合子携带者定义了一个独特的糖尿病患者亚组，这些患者患有早发性非自身免疫性糖尿病，他们对糖尿病治疗反应良好。此外，常见的监管ONECUT1变异与多因素 2 型糖尿病有关。人类多能干细胞的定向分化表明，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结合和增强子活性以及胰腺祖细胞中 NKX2.2/NKX6.1 的表达。总的来说，我们证明 ONECUT1 控制调节内分泌发育的转录和表观遗传机制，涉及一系列糖尿病，包括单基因（隐性和显性）以及多因素遗传。我们的研究结果突出了 ONECUT1 在糖尿病发病机制中的广泛贡献，标志着迈向精准糖尿病医学的重要一步。