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

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 t...

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Main 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
Other Authors: School of Biological Sciences
Format: Article
Language:English
Published: 2024
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Online Access:https://hdl.handle.net/10356/173811
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Institution: Nanyang Technological University
Language: English
id sg-ntu-dr.10356-173811
record_format dspace
institution Nanyang Technological University
building NTU Library
continent Asia
country Singapore
Singapore
content_provider NTU Library
collection DR-NTU
language English
topic Medicine, Health and Life Sciences
Glucagon
Hemoglobin A1c
spellingShingle Medicine, Health and Life Sciences
Glucagon
Hemoglobin A1c
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
PAX4 loss of function increases diabetes risk by altering human pancreatic endocrine cell development
description 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.
author2 School of Biological Sciences
author_facet School of Biological Sciences
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
format Article
author 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
author_sort Lau, Hwee Hui
title PAX4 loss of function increases diabetes risk by altering human pancreatic endocrine cell development
title_short PAX4 loss of function increases diabetes risk by altering human pancreatic endocrine cell development
title_full PAX4 loss of function increases diabetes risk by altering human pancreatic endocrine cell development
title_fullStr PAX4 loss of function increases diabetes risk by altering human pancreatic endocrine cell development
title_full_unstemmed PAX4 loss of function increases diabetes risk by altering human pancreatic endocrine cell development
title_sort pax4 loss of function increases diabetes risk by altering human pancreatic endocrine cell development
publishDate 2024
url https://hdl.handle.net/10356/173811
_version_ 1794549336824086528
spelling sg-ntu-dr.10356-1738112024-03-04T15:32:17Z PAX4 loss of function increases diabetes risk by altering human pancreatic endocrine cell development 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 School of Biological Sciences Lee Kong Chian School of Medicine (LKCMedicine) Institute of Molecular and Cell Biology, A*STAR Medicine, Health and Life Sciences Glucagon Hemoglobin A1c 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. Agency for Science, Technology and Research (A*STAR) Published version We thank the Oxford Genomics Centre at the Wellcome Centre for Human Genetics (funded by Wellcome Trust grant reference 203141/Z/16/Z) for the generation and initial processing of the sequencing data. Data used in this manuscript has received funding from the Innovative Medicines Initiative Joint Undertaking under Grant Agreement number 115439 (StemBANCC), resources of which are composed of financial contribution from the European Union’s Seventh Framework Programme (FP7/2007–2013) and EFPIA companies in kind contribution. H.H.L. is supported by the Institute of Molecular and Cell Biology (IMCB) Scientific Staff Development Award (SSDA) for her parttime Ph.D. N.A.J.K. is supported by the Stanford Maternal and Child Health Research Institute Postdoctoral Fellowship. A.L.G. is a Wellcome Senior Fellow in Basic Biomedical Science. A.L.G. is funded by the Wellcome (200837) and National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) (U01-DK105535, U01-DK085545, UM1DK126185, U01DK123743, U24DK098085) and the Stanford Diabetes Research Center (NIDDK award P30DK116074). A.K.K.T. is supported by IMCB, A*STAR, Lee Foundation Grant SHTX/LFG/002/2018, FY2019 SingHealth Duke-NUS Surgery Academic Clinical Programme Research Support Programme Grant, Precision Medicine and Personalized Therapeutics Joint Research Grant 2019, the 2nd A*STAR-AMED Joint Grant Call 192B9002, HLTRP/2022/NUS-IMCB-02, Paris-NUS 2021-06-R/UP-NUS (ANR-18-IDEX-0001), OFIRG21jun-0097, CSASI21jun-0006, MTCIRG21- 0071, SDDC/FY2021/EX/93-A147, FY 2022 Interstellar Initiative Beyond grant, H22G0a0005 and I22D1AG053. 2024-02-28T06:18:37Z 2024-02-28T06:18:37Z 2023 Journal Article Lau, H. H., Krentz, N. A. J., Abaitua, F., Perez-Alcantara, M., Chan, J., Ajeian, J., Ghosh, S., Lee, Y., Yang, J., Thaman, S., Champon, B., Sun, H., Jha, A., Hoon, S., Tan, N. S., Gardner, D. S., Kao, S. L., Tai, E. S., Gloyn, A. L. & Teo, A. K. K. (2023). PAX4 loss of function increases diabetes risk by altering human pancreatic endocrine cell development. Nature Communications, 14(1), 6119-. https://dx.doi.org/10.1038/s41467-023-41860-z 2041-1723 https://hdl.handle.net/10356/173811 10.1038/s41467-023-41860-z 37777536 2-s2.0-85172824146 1 14 6119 en Nature Communications © 2023 The Author(s). This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. 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