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Characterization of a knock-in mouse model of the homozygous p.V37I variant in Gjb2
The homozygous p.V37I variant in GJB2 is prevalent in East and Southeast Asians and may lead to mild-to-moderate hearing loss with reduced penetrance. To investigate the pathogenic mechanism underlying this variant, we generated a knock-in mouse model of homozygous p.V37I by an embryonic stem cell g...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5020688/ https://www.ncbi.nlm.nih.gov/pubmed/27623246 http://dx.doi.org/10.1038/srep33279 |
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author | Chen, Ying Hu, Lingxiang Wang, Xueling Sun, Changling Lin, Xin li, Lei Mei, Ling Huang, Zhiwu Yang, Tao Wu, Hao |
author_facet | Chen, Ying Hu, Lingxiang Wang, Xueling Sun, Changling Lin, Xin li, Lei Mei, Ling Huang, Zhiwu Yang, Tao Wu, Hao |
author_sort | Chen, Ying |
collection | PubMed |
description | The homozygous p.V37I variant in GJB2 is prevalent in East and Southeast Asians and may lead to mild-to-moderate hearing loss with reduced penetrance. To investigate the pathogenic mechanism underlying this variant, we generated a knock-in mouse model of homozygous p.V37I by an embryonic stem cell gene targeting method. Auditory brainstem response test showed that the knock-in mice developed progressive, mild-to-moderate hearing loss over the first 4–9 months. Overall no significant developmental and morphological abnormality was observed in the knock-in mouse cochlea, while confocal immunostaining and electron microscopic scanning revealed minor loss of the outer hair cells. Gene expression microarray analysis identified 105 up-regulated and 43 down-regulated genes in P5 knock-in mouse cochleae (P < 0.05 adjusted by the Benjamini & Hochberg method), among which four top candidate genes with the highest fold-changes or implication to deafness Fcer1g, Nnmt and Lars2 and Cuedc1 were verified by quantitative real-time PCR. Our study demonstrated that the homozygous p.V37I knock-in mouse modeled the hearing phenotype of the human patients and can serve as a useful animal model for further studies. The differentially expressed genes identified in this study may shed new insights into the understanding of the pathogenic mechanism and the phenotypic modification of homozygous p.V37I. |
format | Online Article Text |
id | pubmed-5020688 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-50206882016-09-20 Characterization of a knock-in mouse model of the homozygous p.V37I variant in Gjb2 Chen, Ying Hu, Lingxiang Wang, Xueling Sun, Changling Lin, Xin li, Lei Mei, Ling Huang, Zhiwu Yang, Tao Wu, Hao Sci Rep Article The homozygous p.V37I variant in GJB2 is prevalent in East and Southeast Asians and may lead to mild-to-moderate hearing loss with reduced penetrance. To investigate the pathogenic mechanism underlying this variant, we generated a knock-in mouse model of homozygous p.V37I by an embryonic stem cell gene targeting method. Auditory brainstem response test showed that the knock-in mice developed progressive, mild-to-moderate hearing loss over the first 4–9 months. Overall no significant developmental and morphological abnormality was observed in the knock-in mouse cochlea, while confocal immunostaining and electron microscopic scanning revealed minor loss of the outer hair cells. Gene expression microarray analysis identified 105 up-regulated and 43 down-regulated genes in P5 knock-in mouse cochleae (P < 0.05 adjusted by the Benjamini & Hochberg method), among which four top candidate genes with the highest fold-changes or implication to deafness Fcer1g, Nnmt and Lars2 and Cuedc1 were verified by quantitative real-time PCR. Our study demonstrated that the homozygous p.V37I knock-in mouse modeled the hearing phenotype of the human patients and can serve as a useful animal model for further studies. The differentially expressed genes identified in this study may shed new insights into the understanding of the pathogenic mechanism and the phenotypic modification of homozygous p.V37I. Nature Publishing Group 2016-09-13 /pmc/articles/PMC5020688/ /pubmed/27623246 http://dx.doi.org/10.1038/srep33279 Text en Copyright © 2016, The Author(s) http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Chen, Ying Hu, Lingxiang Wang, Xueling Sun, Changling Lin, Xin li, Lei Mei, Ling Huang, Zhiwu Yang, Tao Wu, Hao Characterization of a knock-in mouse model of the homozygous p.V37I variant in Gjb2 |
title | Characterization of a knock-in mouse model of the homozygous p.V37I variant in Gjb2 |
title_full | Characterization of a knock-in mouse model of the homozygous p.V37I variant in Gjb2 |
title_fullStr | Characterization of a knock-in mouse model of the homozygous p.V37I variant in Gjb2 |
title_full_unstemmed | Characterization of a knock-in mouse model of the homozygous p.V37I variant in Gjb2 |
title_short | Characterization of a knock-in mouse model of the homozygous p.V37I variant in Gjb2 |
title_sort | characterization of a knock-in mouse model of the homozygous p.v37i variant in gjb2 |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5020688/ https://www.ncbi.nlm.nih.gov/pubmed/27623246 http://dx.doi.org/10.1038/srep33279 |
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