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A common NHE3 single-nucleotide polymorphism has normal function and sensitivity to regulatory ligands.

Jianyi Yin1, Chung-Ming Tse1, Boyoung Cha1

  • 1Department of Medicine, Division of Gastroenterology, Johns Hopkins University School of Medicine, Baltimore, Maryland.

American Journal of Physiology. Gastrointestinal and Liver Physiology
|May 13, 2017
PubMed
Summary

The common NHE3-799C variant, prevalent in Asian populations, shows no significant functional impairment or altered regulation in humans, suggesting limited clinical disease association. This study investigates its population distribution and functional impact.

Keywords:
NHE3SNPdiarrheaphenotypepolymorphism

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Area of Science:

  • Molecular Biology
  • Genetics
  • Physiology

Background:

  • The Na+/H+ exchanger NHE3 (encoded by SLC9A3) is crucial for sodium absorption in the intestines and kidneys.
  • NHE3 dysfunction is linked to diarrheal diseases, and numerous single-nucleotide polymorphisms (SNPs) exist in its gene.
  • The nonsynonymous SNP rs2247114-G>A, resulting in an arginine to cysteine substitution at amino acid 799 (NHE3-799C), is common in Asian populations.

Purpose of the Study:

  • To determine the population distribution of the NHE3-799C polymorphism across different ethnic groups.
  • To assess the functional significance and clinical relevance of the human NHE3-799C variant.
  • To characterize the sensitivity of NHE3-799C to regulatory ligands and a novel inhibitor, tenapanor.

Main Methods:

  • Bioinformatics analyses were used to investigate the allele frequency of NHE3-799C in various ethnic populations.
  • A cohort of Japanese patients with cardiovascular or renal disease was analyzed.
  • In vitro studies using fibroblasts expressing human NHE3-799C or NHE3-799R were conducted to assess protein expression, surface localization, basal activity, and response to regulatory ligands and tenapanor.

Main Results:

  • NHE3-799C allele frequencies were highest in Asian populations (29.5-57.6%), followed by European (11.1-23.6%) and African (10.2-22.7%) populations.
  • Cells expressing NHE3-799C showed lower total protein but higher surface expression compared to NHE3-799R.
  • NHE3-799C exhibited similar basal activity and regulation by serum or forskolin as NHE3-799R; tenapanor inhibited both variants with nanomolar IC50 values, though significantly different.

Conclusions:

  • NHE3-799C is a common human variant, particularly prevalent in Asian populations.
  • The variant does not appear to compromise NHE3 function or its regulation by common stimuli.
  • NHE3-799C is unlikely to be a major contributor to clinical disease, despite its altered expression and sensitivity to tenapanor.