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A Standard Methodology to Examine On-site Mutagenicity As a Function of Point Mutation Repair Catalyzed by CRISPR/Cas9 and SsODN in Human Cells
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Functional characterization of SLC26A3 c.392C>G (p.P131R) mutation in intestinal barrier function using

Nini Zhang1,2,3,4, Daniel P Heruth2, Weibin Wu2,3,5

  • 11Division of Gastroenterology, Department of Pediatrics, Children's Mercy Hospitals and Clinics, Kansas City, MO USA.

Cell & Bioscience
|May 23, 2019
PubMed

Insights

Congenital chloride diarrhea (CCD) is linked to the SLC26A3 rs386833481 gene variant, which impairs epithelial barrier function. This genetic defect disrupts SLC26A3 expression and protein interactions, leading to increased intestinal permeability.

Area of Science:

  • Gastroenterology
  • Genetics
  • Molecular Biology

Background:

  • Congenital chloride diarrhea (CCD) is a rare, life-threatening neonatal disorder.
  • Early diagnosis and treatment are crucial to prevent severe dehydration and mortality.
  • The SLC26A3 rs386833481 gene polymorphism is a significant genetic factor in CCD development.

Purpose of the Study:

  • To investigate the impact of the SLC26A3 rs386833481 gene polymorphism on epithelial barrier function.
  • To elucidate the molecular mechanisms underlying the effects of this variant on epithelial cells.

Main Methods:

  • Utilized human colonic Caco-2 and mouse colonic CMT-93 cell lines.
  • Assessed epithelial barrier function in cells expressing wild-type and variant P131R-SLC26A3.
  • Investigated molecular mechanisms including SLC26A3 expression, ubiquitination, and protein interactions (ZO-1/CFTR).

Main Results:

  • The P131R-SLC26A3 variant significantly increased epithelial barrier dysfunction compared to wild-type SLC26A3.
  • Restoration of wild-type SLC26A3 reversed the observed barrier dysfunction.
  • Mechanistically, the variant decreased SLC26A3 expression via ubiquitination and disrupted ZO-1/CFTR interactions, increasing permeability.

Conclusions:

  • SLC26A3 rs386833481 is identified as a likely causative mutation for epithelial barrier dysfunction in CCD.
  • This SNP plays a role in regulating epithelial permeability.
  • Therapeutic strategies targeting this SNP or enhancing SLC26A3 function may benefit patients with chronic diarrhea diseases.
Abstract

Keywords:
Chloride transportEpithelial cellInflammationIntestinal epitheliumSingle-nucleotide polymorphism (SNP)

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