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

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.