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Functional characterization of SLC26A3 c.392C>G (p.P131R) mutation in intestinal barrier function using CRISPR/CAS9-created cell models

BACKGROUND: Congenital chloride diarrhea (CCD) in a newborn is a rare autosomal recessive disorder with life-threatening complications, requiring early diagnostics and treatment to prevent severe dehydration and infant mortality. SLC26A3 rs386833481 (c.392C>G; p.P131R) gene polymorphism is an imp...

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Autores principales: Zhang, Nini, Heruth, Daniel P., Wu, Weibin, Zhang, Li Qin, Nsumu, Marianne N., Shortt, Katherine, Li, Kelvin, Jiang, Xun, Wang, Baoxi, Friesen, Craig, Li, Ding-You, Ye, Shui Qing
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BioMed Central 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518688/
https://www.ncbi.nlm.nih.gov/pubmed/31114672
http://dx.doi.org/10.1186/s13578-019-0303-1
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author Zhang, Nini
Heruth, Daniel P.
Wu, Weibin
Zhang, Li Qin
Nsumu, Marianne N.
Shortt, Katherine
Li, Kelvin
Jiang, Xun
Wang, Baoxi
Friesen, Craig
Li, Ding-You
Ye, Shui Qing
author_facet Zhang, Nini
Heruth, Daniel P.
Wu, Weibin
Zhang, Li Qin
Nsumu, Marianne N.
Shortt, Katherine
Li, Kelvin
Jiang, Xun
Wang, Baoxi
Friesen, Craig
Li, Ding-You
Ye, Shui Qing
author_sort Zhang, Nini
collection PubMed
description BACKGROUND: Congenital chloride diarrhea (CCD) in a newborn is a rare autosomal recessive disorder with life-threatening complications, requiring early diagnostics and treatment to prevent severe dehydration and infant mortality. SLC26A3 rs386833481 (c.392C>G; p.P131R) gene polymorphism is an important genetic determinant of CCD. Here, we report the influence of the non-synonymous SLC26A3 variant rs386833481 gene polymorphism on the function of the epithelial barrier and the potential mechanisms of these effects. RESULTS: We found that P131R-SLC26A3 increased dysfunction of the epithelial barrier compared with wild type SLC26A3 in human colonic Caco-2 and mouse colonic CMT-93 cells. When P131R-SLC26A3 was subsequently reverted to wild type, the epithelial barrier function was restored similar to wild type cells. Further study demonstrated that variant P131R-SLC26A3 disrupts function of epithelial barrier through two distinct molecular mechanisms: (a) decreasing SLC26A3 expression through a ubiquitination pathway and (b) disrupting a key interaction with its partner ZO-1/CFTR, thereby increasing the epithelial permeability. CONCLUSION: Our study provides an important insight of SLC26A3 SNPs in the regulation of the epithelial permeability and indicates that SLC26A3 rs386833481 is likely a causative mutation in the dysfunction of epithelial barrier of CCD, and correction of this SNP or increasing SLC26A3 function could be therapeutically beneficial for chronic diarrhea diseases.
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spelling pubmed-65186882019-05-21 Functional characterization of SLC26A3 c.392C>G (p.P131R) mutation in intestinal barrier function using CRISPR/CAS9-created cell models Zhang, Nini Heruth, Daniel P. Wu, Weibin Zhang, Li Qin Nsumu, Marianne N. Shortt, Katherine Li, Kelvin Jiang, Xun Wang, Baoxi Friesen, Craig Li, Ding-You Ye, Shui Qing Cell Biosci Research BACKGROUND: Congenital chloride diarrhea (CCD) in a newborn is a rare autosomal recessive disorder with life-threatening complications, requiring early diagnostics and treatment to prevent severe dehydration and infant mortality. SLC26A3 rs386833481 (c.392C>G; p.P131R) gene polymorphism is an important genetic determinant of CCD. Here, we report the influence of the non-synonymous SLC26A3 variant rs386833481 gene polymorphism on the function of the epithelial barrier and the potential mechanisms of these effects. RESULTS: We found that P131R-SLC26A3 increased dysfunction of the epithelial barrier compared with wild type SLC26A3 in human colonic Caco-2 and mouse colonic CMT-93 cells. When P131R-SLC26A3 was subsequently reverted to wild type, the epithelial barrier function was restored similar to wild type cells. Further study demonstrated that variant P131R-SLC26A3 disrupts function of epithelial barrier through two distinct molecular mechanisms: (a) decreasing SLC26A3 expression through a ubiquitination pathway and (b) disrupting a key interaction with its partner ZO-1/CFTR, thereby increasing the epithelial permeability. CONCLUSION: Our study provides an important insight of SLC26A3 SNPs in the regulation of the epithelial permeability and indicates that SLC26A3 rs386833481 is likely a causative mutation in the dysfunction of epithelial barrier of CCD, and correction of this SNP or increasing SLC26A3 function could be therapeutically beneficial for chronic diarrhea diseases. BioMed Central 2019-05-14 /pmc/articles/PMC6518688/ /pubmed/31114672 http://dx.doi.org/10.1186/s13578-019-0303-1 Text en © The Author(s) 2019 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided 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 Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
spellingShingle Research
Zhang, Nini
Heruth, Daniel P.
Wu, Weibin
Zhang, Li Qin
Nsumu, Marianne N.
Shortt, Katherine
Li, Kelvin
Jiang, Xun
Wang, Baoxi
Friesen, Craig
Li, Ding-You
Ye, Shui Qing
Functional characterization of SLC26A3 c.392C>G (p.P131R) mutation in intestinal barrier function using CRISPR/CAS9-created cell models
title Functional characterization of SLC26A3 c.392C>G (p.P131R) mutation in intestinal barrier function using CRISPR/CAS9-created cell models
title_full Functional characterization of SLC26A3 c.392C>G (p.P131R) mutation in intestinal barrier function using CRISPR/CAS9-created cell models
title_fullStr Functional characterization of SLC26A3 c.392C>G (p.P131R) mutation in intestinal barrier function using CRISPR/CAS9-created cell models
title_full_unstemmed Functional characterization of SLC26A3 c.392C>G (p.P131R) mutation in intestinal barrier function using CRISPR/CAS9-created cell models
title_short Functional characterization of SLC26A3 c.392C>G (p.P131R) mutation in intestinal barrier function using CRISPR/CAS9-created cell models
title_sort functional characterization of slc26a3 c.392c>g (p.p131r) mutation in intestinal barrier function using crispr/cas9-created cell models
topic Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6518688/
https://www.ncbi.nlm.nih.gov/pubmed/31114672
http://dx.doi.org/10.1186/s13578-019-0303-1
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