Small molecules restore the function of mutant CLC5 associated with Dent disease

J Cell Mol Med. 2021 Jan;25(2):1319-1322. doi: 10.1111/jcmm.16091. Epub 2020 Nov 16.

Abstract

Dent disease type 1 is caused by mutations in the CLCN5 gene that encodes CLC5, a 2Cl- /H+ exchanger. The CLC5 mutants that have been functionally analysed constitute three major classes based on protein expression, cellular localization and channel function. We tested two small molecules, 4-phenylbutyrate (4PBA) and its analogue 2-naphthoxyacetic acid (2-NOAA), for their effect on mutant CLC5 function and expression by whole-cell patch-clamp and Western blot, respectively. The expression and function of non-Class I CLC5 mutants that have reduced function could be restored by either treatment. Cell viability was reduced in cells treated with 2-NOAA. 4PBA is a FDA-approved drug for the treatment of urea cycle disorders and offers a potential therapy for Dent disease.

Keywords: CLCN5; 2-naphthoxyacetic acid (2-NOAA); 4-phenylbutyrate (4PBA); CLC5; dent disease.

MeSH terms

  • Cell Survival / drug effects
  • Chemokine CCL5 / genetics*
  • Chemokine CCL5 / metabolism
  • Dent Disease / genetics*
  • Glycolates / pharmacology
  • HEK293 Cells
  • Humans
  • Mutation / genetics*
  • Phenylbutyrates / pharmacology
  • Small Molecule Libraries / pharmacology*

Substances

  • Chemokine CCL5
  • Glycolates
  • Phenylbutyrates
  • Small Molecule Libraries
  • 2-naphthoxyacetic acid
  • 4-phenylbutyric acid