PAX4 loss of function increases diabetes risk by altering human pancreatic endocrine cell development

Hwee Hui Lau, Nicole A. J. Krentz, Fernando Abaitua, Marta Perez-Alcantara, Jun-Wei Chan, Jila Ajeian, Soumita Ghosh, Yunkyeong Lee, Jing Yang, Swaraj Thaman, Benoite Champon, Han Sun, Alokkumar Jha, Shawn Hoon, Nguan Soon Tan, Daphne Su-Lyn Gardner, Shih Ling Kao, E. Shyong Tai, Anna L. Gloyn () and Adrian Kee Keong Teo ()
Additional contact information
Hwee Hui Lau: Agency for Science, Technology and Research (A*STAR)
Nicole A. J. Krentz: Stanford University School of Medicine
Fernando Abaitua: University of Oxford
Marta Perez-Alcantara: University of Oxford
Jun-Wei Chan: Agency for Science, Technology and Research (A*STAR)
Jila Ajeian: University of Oxford
Soumita Ghosh: National University of Singapore
Yunkyeong Lee: Stanford University School of Medicine
Jing Yang: Stanford University School of Medicine
Swaraj Thaman: Stanford University School of Medicine
Benoite Champon: University of Oxford
Han Sun: Stanford University School of Medicine
Alokkumar Jha: Stanford University School of Medicine
Shawn Hoon: Agency for Science, Technology and Research (A*STAR)
Nguan Soon Tan: Nanyang Technological University
Daphne Su-Lyn Gardner: Singapore General Hospital
Shih Ling Kao: National University Hospital and National University Health System
E. Shyong Tai: National University Hospital and National University Health System
Anna L. Gloyn: Stanford University School of Medicine
Adrian Kee Keong Teo: Agency for Science, Technology and Research (A*STAR)

Nature Communications, 2023, vol. 14, issue 1, 1-19

Abstract: Abstract The coding variant (p.Arg192His) in the transcription factor PAX4 is associated with an altered risk for type 2 diabetes (T2D) in East Asian populations. In mice, Pax4 is essential for beta cell formation but its role on human beta cell development and/or function is unknown. Participants carrying the PAX4 p.His192 allele exhibited decreased pancreatic beta cell function compared to homozygotes for the p.192Arg allele in a cross-sectional study in which we carried out an intravenous glucose tolerance test and an oral glucose tolerance test. In a pedigree of a patient with young onset diabetes, several members carry a newly identified p.Tyr186X allele. In the human beta cell model, EndoC-βH1, PAX4 knockdown led to impaired insulin secretion, reduced total insulin content, and altered hormone gene expression. Deletion of PAX4 in human induced pluripotent stem cell (hiPSC)-derived islet-like cells resulted in derepression of alpha cell gene expression. In vitro differentiation of hiPSCs carrying PAX4 p.His192 and p.X186 risk alleles exhibited increased polyhormonal endocrine cell formation and reduced insulin content that can be reversed with gene correction. Together, we demonstrate the role of PAX4 in human endocrine cell development, beta cell function, and its contribution to T2D-risk.

Date: 2023
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DOI: 10.1038/s41467-023-41860-z

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