Mutations in the thyroid hormone (TH) transporter monocarboxylate transporter 8 (MCT8) result in severe intellectual and motor disability. At present, no effective therapy is available to restore TH signaling in MCT8-dependent tissues. Recent in vitro studies in stable overexpression cell models suggested that the function of certain mutant MCT8 proteins, specifically those that affect protein stability and intracellular trafficking (e.g., p.F501del), could be partially recovered by chemical chaperones. However, the effects of chaperones have not been demonstrated in other commonly used models for MCT8 deficiency, including transient overexpression models and patient-derived fibroblasts. Here, we demonstrate that the chemical chaperone 4-phenylbutyric acid (PBA) similarly potentiates the T3 transport function of wild-type and p.F501del mutant MCT8 in transiently transfected COS-1 cells by increasing MCT8 messenger RNA, total protein, and cell surface expression levels. Although PBA also increased the cell surface expression levels of the p.R445L mutant, no functional improvement was observed, which is in line with the proposed important role of Arg445 in substrate translocation. In contrast, PBA showed only minimal effects in ex vivo studies using control or p.F501del patient-derived fibroblasts. Moreover, the MCT8-specific inhibitor silychristin did not change these minimal effects, suggesting that the underlying mechanism is unrelated to the rescue of functional MCT8. Together, these findings indicate that the potency of chaperones to rescue mutant MCT8 function strongly depends on the cellular model and stress the need for further preclinical studies before clinically available chaperones should be considered as a treatment option in patients with MCT8 deficiency.

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Journal Endocrinology
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Groeneweg, S, van den Berge, A.P.J, Meima, M.E, Peeters, R.P, Visser, T.J, & Visser, W.E. (2018). Effects of Chemical Chaperones on Thyroid Hormone Transport by MCT8 Mutants in Patient-Derived Fibroblasts. Endocrinology, 159(3), 1290–1302. doi:10.1210/en.2017-00846