Atypical KCNQ1/Kv7 channel function in a neonatal diabetes patient: Hypersecretion preceded the failure of pancreatic 8-cells

Zhou, Zhimin1; Gong, Maolian1; Pande, Amit1; Margineanu, Anca1; Lisewski, Ulrike2,3; Purfuerst, Bettina1; Zhu, Han6,7; Liang, Lei4; Jia, Shiqi5; Froehler, Sebastian1; Zeng, Chun6,7; Kuehnen, Peter10; Khodaverdi, Semik8; Krill, Winfried8; Roepke, Torsten2,3; Chen, Wei9; Raile, Klemens10; Sander, Maike1,6,7; Izsvak, Zsuzsanna1

2024-07-19

10.1016/j.isci.2024.110291

ISCIENCE   影响因子和分区

2589-0042

KCNQ1/Kv7, a low -voltage -gated K + channel, regulates cardiac rhythm and glucose homeostasis. While KCNQ1 mutations are associated with long -QT syndrome and type2 diabetes, its function in human pancreatic cells remains controversial. We identified a homozygous KCNQ1 mutation (R397W) in an individual with permanent neonatal diabetes melitus (PNDM) without cardiovascular symptoms. To decipher the potential mechanism(s), we introduced the mutation into human embryonic stem cells and generated islet -like organoids (SC -islets) using CRISPR-mediated homology -repair. The mutation did not affect pancreatic differentiation, but affected channel function by increasing spike frequency and Ca 2+ flux, leading to insulin hypersecretion. With prolonged culturing, the mutant islets decreased their secretion and gradually deteriorated, modeling a diabetic state, which accelerated by high glucose levels. The molecular basis was the downregulated expression of voltage -activated Ca 2+ channels and oxidative phosphorylation. Our study provides a better understanding of the role of KCNQ1 in regulating insulin secretion and b - cell survival in hereditary diabetes pathology.

SCI

英语

其他

National Institutes of Health["R01DK068471","UG3DK122639"]

Science & Technology - Other Topics

Multidisciplinary Sciences

WOS:001264439800001

CELL PRESS

Web of Science

1.Max Delbruck Ctr Mol Med Helmholtz Assoc MDC, D-13125 Berlin, Germany
2.MDC, Expt & Clin Res Ctr ECRC, D-13125 Berlin, Germany
3.Charite, D-13125 Berlin, Germany
4.Anhui Prov Childrens Hosp, Dept Pediat, Hefei 23000, Peoples R China
5.Jinan Univ, Affiliated Hosp 1, Guangzhou 510000, Peoples R China
6.Univ Calif San Diego, Dept Cellular & Mol Med, La Jolla, CA 92037 USA
7.Univ Calif San Diego, Dept Pediat, La Jolla, CA 92037 USA
8.Klinikum Hanau, Dept Pediat, D-63450 Hanau, Germany
9.Southern Univ Sci & Technol, Dept Biol, Shenzhen 518000, Peoples R China
10.Univ Med Berlin, Virchow Klinikum, Charite, D-13125 Berlin, Germany

Zhou, Zhimin,Gong, Maolian,Pande, Amit,et al. Atypical KCNQ1/Kv7 channel function in a neonatal diabetes patient: Hypersecretion preceded the failure of pancreatic 8-cells[J]. ISCIENCE,2024,27(7).

Zhou, Zhimin.,Gong, Maolian.,Pande, Amit.,Margineanu, Anca.,Lisewski, Ulrike.,...&Izsvak, Zsuzsanna.(2024).Atypical KCNQ1/Kv7 channel function in a neonatal diabetes patient: Hypersecretion preceded the failure of pancreatic 8-cells.ISCIENCE,27(7).

Zhou, Zhimin,et al."Atypical KCNQ1/Kv7 channel function in a neonatal diabetes patient: Hypersecretion preceded the failure of pancreatic 8-cells".ISCIENCE 27.7(2024).