Cargando…
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...
Autores principales: | , , , , , , , , , , , |
---|---|
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 |
_version_ | 1783418505883811840 |
---|---|
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. |
format | Online Article Text |
id | pubmed-6518688 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
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 |
work_keys_str_mv | AT zhangnini functionalcharacterizationofslc26a3c392cgpp131rmutationinintestinalbarrierfunctionusingcrisprcas9createdcellmodels AT heruthdanielp functionalcharacterizationofslc26a3c392cgpp131rmutationinintestinalbarrierfunctionusingcrisprcas9createdcellmodels AT wuweibin functionalcharacterizationofslc26a3c392cgpp131rmutationinintestinalbarrierfunctionusingcrisprcas9createdcellmodels AT zhangliqin functionalcharacterizationofslc26a3c392cgpp131rmutationinintestinalbarrierfunctionusingcrisprcas9createdcellmodels AT nsumumariannen functionalcharacterizationofslc26a3c392cgpp131rmutationinintestinalbarrierfunctionusingcrisprcas9createdcellmodels AT shorttkatherine functionalcharacterizationofslc26a3c392cgpp131rmutationinintestinalbarrierfunctionusingcrisprcas9createdcellmodels AT likelvin functionalcharacterizationofslc26a3c392cgpp131rmutationinintestinalbarrierfunctionusingcrisprcas9createdcellmodels AT jiangxun functionalcharacterizationofslc26a3c392cgpp131rmutationinintestinalbarrierfunctionusingcrisprcas9createdcellmodels AT wangbaoxi functionalcharacterizationofslc26a3c392cgpp131rmutationinintestinalbarrierfunctionusingcrisprcas9createdcellmodels AT friesencraig functionalcharacterizationofslc26a3c392cgpp131rmutationinintestinalbarrierfunctionusingcrisprcas9createdcellmodels AT lidingyou functionalcharacterizationofslc26a3c392cgpp131rmutationinintestinalbarrierfunctionusingcrisprcas9createdcellmodels AT yeshuiqing functionalcharacterizationofslc26a3c392cgpp131rmutationinintestinalbarrierfunctionusingcrisprcas9createdcellmodels |