Neonatal diabetes–associated missense PDX1 variant disrupts chromatin association and protein-protein interaction

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.

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Publication Details

Journal
JCI Insight
Published
2025-06-08
DOI
https://doi.org/10.1172/jci.insight.189343
Citations
2
Primary Topic
Pancreatic function and diabetes
Type
article
Field-Weighted Citation Impact
4.01

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article

Neonatal diabetes–associated missense PDX1 variant disrupts chromatin association and protein-protein interaction

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2 citations
JCI Insight
Pancreatic function and diabetes
4.01
article

Neonatal diabetes–associated missense PDX1 variant disrupts chromatin association and protein-protein interaction

Novella Rapini, Fabrizio Barbetti, Doris A. Stoffers, Riccardo Schiaffini, Jeff Ishibashi, Raffaele Iorio, Dario Iafusco, Alessia Piscopo, Angela Zanfardino, Matthew W. Haemmerle, Xiaodun Yang, Stefano Cianfarani, Emanuele Miraglia del Giudice, Mafalda Mucciolo, Bareket Daniel, Maria Cristina Digilio
article en
2 citations

Abstract

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.

JCI InsightVol. 10(11)
University of Rome Tor Vergata (IT), Karolinska Institutet (SE), Bambino Gesù Children's Hospital (IT), University of Campania "Luigi Vanvitelli" (IT), Istituti di Ricovero e Cura a Carattere Scientifico (IT), University of Naples Federico II (IT), University of Pennsylvania (US)
National Institutes of Health
Zero hunger
Openalex Percentile: Top 7%
Pancreatic function and diabetes
4.01
DOIOpen Access PDFOpenAlex
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