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

被引:8
|
作者
Lau, Hwee Hui [1 ,2 ]
Krentz, Nicole A. J. [3 ,4 ,16 ]
Abaitua, Fernando [4 ]
Perez-Alcantara, Marta [4 ]
Chan, Jun-Wei [1 ,2 ]
Ajeian, Jila [5 ]
Ghosh, Soumita [6 ]
Lee, Yunkyeong [3 ]
Yang, Jing [3 ]
Thaman, Swaraj [3 ]
Champon, Benoite [4 ]
Sun, Han [3 ]
Jha, Alokkumar [3 ]
Hoon, Shawn [7 ]
Tan, Nguan Soon [2 ,8 ]
Gardner, Daphne Su-Lyn [9 ]
Kao, Shih Ling [10 ,11 ,12 ]
Tai, E. Shyong [10 ,11 ,12 ,13 ]
Gloyn, Anna L. [3 ,4 ,6 ,14 ]
Teo, Adrian Kee Keong [1 ,12 ,15 ]
机构
[1] ASTAR, Inst Mol & Cell Biol IMCB, Stem Cells & Diabet Lab, Singapore, Singapore
[2] Nanyang Technol Univ, Sch Biol Sci, Singapore, Singapore
[3] Stanford Univ, Sch Med, Dept Pediat, Div Endocrinol, Stanford, CA 94305 USA
[4] Univ Oxford, Wellcome Ctr Human Genet, Oxford, England
[5] Univ Oxford, Oxford Ctr Diabet Endocrinol & Metab, Oxford, England
[6] Natl Univ Singapore, Canc Sci Inst Singapore, Singapore, Singapore
[7] ASTAR, Inst Mol & Cell Biol IMCB, Mol Engn Lab, Singapore, Singapore
[8] Nanyang Technol Univ, Lee Kong Chian Sch Med, Singapore, Singapore
[9] Singapore Gen Hosp, Dept Endocrinol, Singapore, Singapore
[10] Natl Univ Singapore Hosp, Dept Med, Singapore, Singapore
[11] Natl Univ Hlth Syst, Singapore, Singapore
[12] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Med, Singapore, Singapore
[13] Natl Univ Singapore, Saw Swee Hock Sch Publ Hlth, Singapore, Singapore
[14] Stanford Univ, Stanford Diabet Res Ctr, Stanford, CA 94305 USA
[15] Natl Univ Singapore, Yong Loo Lin Sch Med, Dept Biochem, Singapore, Singapore
[16] Univ British Columbia, Fac Pharmaceut Sci, Vancouver, BC, Canada
基金
英国惠康基金;
关键词
TRANSCRIPTION FACTOR PAX4; SINGLE-CELL; BETA-CELLS; GENE; DEDIFFERENTIATION; MUTATION; ISLETS; ARCHITECTURE; GENERATION; REPRESSOR;
D O I
10.1038/s41467-023-41860-z
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
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-beta H1, 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.
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收藏
页数:19
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