Endocrine Abstracts

Introduction: Monocarboxylate transporter 8 (MCT8) is a thyroid hormone-specific transmembrane transport protein. Inactivating mutations in MCT8 lead to severe mental retardation, the Allan-Herndon-Dudley syndrome. The severity of the Allan-Herndon-Dudley syndrome differs among MCT8 patients. Partial activity of MCT8 can be caused either by mutations affecting the transport mechanism (e.g. substrate interaction, conformational change) or by inefficient protein expression, membrane translocation or stability. The latter MCT8 mutants may be responsive to chemical chaperones which stabilize the protein or support membrane localization. We have previously shown that application of the chemical chaperone sodium phenylbutyrate rescues expression and transport activity of the pathogenic ΔPhe501 mutant in vitro.

Methods: Several mutations were introduced into human MCT8 by site directed mutagenesis and stably transfected into MDCK1 (Madin-Darby canine kidney) cells. The cells were treated with increasing concentrations of chaperones for two days. Western blotting and radioactive thyroid hormone-uptake experiments were performed to analyze chaperone effects.

Results: Here we will show new mutants (e.g. L434W) which are responsive to sodium phenylbutyrate. It increases protein expression and function of various pathogenic MCT8 mutations.

Conclusion: MCT8 mutations do not only affect the transport activity of the protein, but also its stability and localization at the cell surface. Sodium phenylbutyrate is a common drug used for the treatment of urea cycle defects and cystic fibrosis. The administration of chemical chaperones, which are safe for use in humans, could be a new tool for the therapy of MCT8 deficiency to improve the patient’s quality of life.