Yang Xiaodun, Zanfardino Angela, Schiaffini Riccardo, Ishibashi Jeff, Daniel Bareket, Haemmerle Matthew W, Rapini Novella, Piscopo Alessia, Miraglia Del Giudice Emanuele, Digilio Maria Cristina, Iorio Raffaele, Mucciolo Mafalda, Cianfarani Stefano, Iafusco Dario, Barbetti Fabrizio, Stoffers Doris A
Institute for Diabetes, Obesity and Metabolism, Department of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA.
Regional Center for Pediatric Diabetes, Department of Pediatrics, University of Campania Luigi Vanvitelli, Naples, Italy.
JCI Insight. 2025 Jun 9;10(11). doi: 10.1172/jci.insight.189343.
PDX1 mutations are associated with multiple forms of diabetes, including syndromic, neonatal, mature onset diabetes of the young (MODY), and type 2 diabetes. Two PDX1 missense mutations (Thr151Met and Asn196Thr) were identified in a pediatric female patient that cause permanent neonatal diabetes, pancreas hypoplasia, and a malformed gallbladder. We found that the mouse Pdx1 Asn197Thr variant (homologous to human PDX1 Asn196Thr), but not Pdx1 Thr152Met (homologous to human PDX1 Thr151Met), altered its nuclear localization and disrupted the PDX1-ONECUT1 interaction. Neither variant substantially affected PDX1 protein stability, but both reduced PDX1 binding to the Pdx1 gene promoter. Importantly, the Pdx1 Asn197Thr variant caused pancreas agenesis and reduced enteroendocrine cells in the duodenum in genetically engineered mice, due at least in part to reduced Pdx1 promoter binding and disrupted PDX1-ONECUT1 interaction.
PDX1突变与多种形式的糖尿病相关，包括综合征性、新生儿、青年成年起病型糖尿病（MODY）和2型糖尿病。在一名儿科女性患者中鉴定出两种PDX1错义突变（Thr151Met和Asn196Thr），这些突变导致永久性新生儿糖尿病、胰腺发育不全和胆囊畸形。我们发现小鼠Pdx1 Asn197Thr变体（与人类PDX1 Asn196Thr同源），而非Pdx1 Thr152Met（与人类PDX1 Thr151Met同源），改变了其核定位并破坏了PDX1-ONECUT1相互作用。两种变体均未实质性影响PDX1蛋白稳定性，但都降低了PDX1与Pdx1基因启动子的结合。重要的是，Pdx1 Asn197Thr变体在基因工程小鼠中导致胰腺发育不全并减少十二指肠中的肠内分泌细胞，这至少部分归因于Pdx1启动子结合减少和PDX1-ONECUT1相互作用被破坏。
