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Insulin2(Q104del) (Kuma) mutant mice develop diabetes with dominant inheritance
Insulin gene mutations have been identified to cause monogenic diabetes, and most of which developed permanent neonatal diabetes at young ages before 6 months of age in humans. To establish an animal model of permanent diabetes, we performed genome editing using the CRISPR/Cas9 system. We generated...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7376009/ https://www.ncbi.nlm.nih.gov/pubmed/32699230 http://dx.doi.org/10.1038/s41598-020-68987-z |
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author | Sakano, Daisuke Inoue, Airi Enomoto, Takayuki Imasaka, Mai Okada, Seiji Yokota, Mutsumi Koike, Masato Araki, Kimi Kume, Shoen |
author_facet | Sakano, Daisuke Inoue, Airi Enomoto, Takayuki Imasaka, Mai Okada, Seiji Yokota, Mutsumi Koike, Masato Araki, Kimi Kume, Shoen |
author_sort | Sakano, Daisuke |
collection | PubMed |
description | Insulin gene mutations have been identified to cause monogenic diabetes, and most of which developed permanent neonatal diabetes at young ages before 6 months of age in humans. To establish an animal model of permanent diabetes, we performed genome editing using the CRISPR/Cas9 system. We generated a novel Kuma mutant mice with p.Q104del in the Insulin2 (Ins2) gene in a BRJ background that exhibits a severe immune deficiency. Kuma mutant mice are non-obese and developed hyperglycemia from 3 weeks after birth in both males and females, which are inherited in a dominant mode. Kuma mutant mice displayed reduced insulin protein levels from 3-weeks-old, which seem to be caused by the low stability of the mutant insulin protein. Kuma mutant showed a reduction in islet size and islet mass. Electron microscopic analysis revealed a marked decrease in the number and size of insulin granules in the beta-cells of the mutant mice. Hyperglycemia of the mutant can be rescued by insulin administration. Our results present a novel insulin mutation that causes permanent early-onset diabetes, which provides a model useful for islet transplantation studies. |
format | Online Article Text |
id | pubmed-7376009 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
spelling | pubmed-73760092020-07-24 Insulin2(Q104del) (Kuma) mutant mice develop diabetes with dominant inheritance Sakano, Daisuke Inoue, Airi Enomoto, Takayuki Imasaka, Mai Okada, Seiji Yokota, Mutsumi Koike, Masato Araki, Kimi Kume, Shoen Sci Rep Article Insulin gene mutations have been identified to cause monogenic diabetes, and most of which developed permanent neonatal diabetes at young ages before 6 months of age in humans. To establish an animal model of permanent diabetes, we performed genome editing using the CRISPR/Cas9 system. We generated a novel Kuma mutant mice with p.Q104del in the Insulin2 (Ins2) gene in a BRJ background that exhibits a severe immune deficiency. Kuma mutant mice are non-obese and developed hyperglycemia from 3 weeks after birth in both males and females, which are inherited in a dominant mode. Kuma mutant mice displayed reduced insulin protein levels from 3-weeks-old, which seem to be caused by the low stability of the mutant insulin protein. Kuma mutant showed a reduction in islet size and islet mass. Electron microscopic analysis revealed a marked decrease in the number and size of insulin granules in the beta-cells of the mutant mice. Hyperglycemia of the mutant can be rescued by insulin administration. Our results present a novel insulin mutation that causes permanent early-onset diabetes, which provides a model useful for islet transplantation studies. Nature Publishing Group UK 2020-07-22 /pmc/articles/PMC7376009/ /pubmed/32699230 http://dx.doi.org/10.1038/s41598-020-68987-z Text en © The Author(s) 2020 Open Access 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. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/. |
spellingShingle | Article Sakano, Daisuke Inoue, Airi Enomoto, Takayuki Imasaka, Mai Okada, Seiji Yokota, Mutsumi Koike, Masato Araki, Kimi Kume, Shoen Insulin2(Q104del) (Kuma) mutant mice develop diabetes with dominant inheritance |
title | Insulin2(Q104del) (Kuma) mutant mice develop diabetes with dominant inheritance |
title_full | Insulin2(Q104del) (Kuma) mutant mice develop diabetes with dominant inheritance |
title_fullStr | Insulin2(Q104del) (Kuma) mutant mice develop diabetes with dominant inheritance |
title_full_unstemmed | Insulin2(Q104del) (Kuma) mutant mice develop diabetes with dominant inheritance |
title_short | Insulin2(Q104del) (Kuma) mutant mice develop diabetes with dominant inheritance |
title_sort | insulin2(q104del) (kuma) mutant mice develop diabetes with dominant inheritance |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7376009/ https://www.ncbi.nlm.nih.gov/pubmed/32699230 http://dx.doi.org/10.1038/s41598-020-68987-z |
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