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

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.

SUBMITTER: Liu J

PROVIDER: S-EPMC7812281 | biostudies-literature | 2020 Nov

REPOSITORIES: biostudies-literature

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

Liu Jingshu J Sadeh Tal T TT Lippiat Jonathan D JD Thakker Rajesh V RV Black Graeme C GC Manson Forbes F

Journal of cellular and molecular medicine 20201116 2

Dent disease type 1 is caused by mutations in the CLCN5 gene that encodes CLC5, a 2Cl<sup>-</sup> /H<sup>+</sup> 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. ...[more]

PMID: 33200471

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