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- Title
PAX4 loss of function increases diabetes risk by altering human pancreatic endocrine cell development.
- Authors
Lau, Hwee Hui; Krentz, Nicole A. J.; Abaitua, Fernando; Perez-Alcantara, Marta; Chan, Jun-Wei; Ajeian, Jila; Ghosh, Soumita; Lee, Yunkyeong; Yang, Jing; Thaman, Swaraj; Champon, Benoite; Sun, Han; Jha, Alokkumar; Hoon, Shawn; Tan, Nguan Soon; Gardner, Daphne Su-Lyn; Kao, Shih Ling; Tai, E. Shyong; Gloyn, Anna L.; Teo, Adrian Kee Keong
- 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. A coding variant of the PAX4 transcription factor (p.Arg192His) is uniquely associated with Type 2 Diabetes in East Asian populations. Here, the authors show that two different coding gene variants of PAX4, p.Arg192His and the newly identified p.Tyr186X, can influence pancreatic beta cell development, identity, and function.
- Subjects
INDUCED pluripotent stem cells; EAST Asians; GLUCOSE tolerance tests; PANCREATIC beta cells; TYPE 2 diabetes
- Publication
Nature Communications, 2023, Vol 14, Issue 1, p1
- ISSN
2041-1723
- Publication type
Article
- DOI
10.1038/s41467-023-41860-z