Gene expression profiles of fibroblasts from MCT8 patients
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE20538 | GEO | 2010/08/23
SECONDARY ACCESSION(S): PRJNA125289
REPOSITORIES: GEO
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Project description:The monocarboxylate transporter 8 (Mct8) protein is a primary T4 and T3 (TH) transporter. Mutations of the MCT8-encoding, SLC16A2 gene alters thyroid function and thyroid hormone metabolism, and severely impairs neurodevelopment (Allan-Herndon-Dudley syndrome, AHDS). Mct8-deficient mice manifest thyroid alterations but lack neurological signs. It is thought that Mct8 deficiency in mice is compensated by T4 transport through the Slco1c1-encoded organic anion transporter polypeptide 1c1 (Oatp1c1). This allows local brain generation of sufficient T3 by the Dio2-encoded type 2 deiodinase (D2). The Slc16a2/Slco1c1 (MO) and Slc16a2/Dio2 (MD) double knock out mice lacking T4 and T3 transport, or T3 transport and T4 deiodination, would be more approriate models of AHDS. The goal of this work was to compare the cerebral hypothyroidism of systemic hypothyroidism (SH) caused by thyroid gland blockade with that present in the double KOs.
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Project description:Patients with mutations in the thyroid hormone (TH) cell transporter MCT8 gene develop severe neuropsychomotor retardation known as the Allan-Herndon-Dudley syndrome (AHDS). It is assumed that this is caused by a reduction in TH signaling in the developing brain during both intrauterine and postnatal developmental stages, and treatment remains understandably challenging. Given species differences in brain TH transporters and the limitations of studies in mice, we generated cerebral organoids (COs) using human iPSCs from MCT8-deficient patients. We found that MCT8-deficient COs exhibit (i) alterations in early neurodevelopment, resulting in smaller neural rosettes with thinner cortical units, (ii) impaired T3 transport in developing neural cells, as assessed through deiodinase-3-mediated T3 catabolism, (iii) reduced expression of genes involved in cerebral cortex development, and (iv) reduced T3-inducibility of TH-regulated genes. In contrast, the TH-analogs 3,5-diiodothyropropionic acid and 3,3’,5-triiodothyroacetic acid triggered normal responses (induction/repression of T3-responsive genes) in MCT8-deficient COs, constituting a proof-of-concept that lack of T3 transport underlies the pathophysiology of AHDS, and demonstrating the clinical potential for TH analogues to be used in treating AHDS patients. MCT8-deficient COs represent a species-specific relevant preclinical model that can be utilized to screen drugs with potential benefits as personalized therapeutics for AHDS patients.
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Project description:Monocarboxylate transporter 8 (MCT8) deficiency is a rare genetic disease leading to a severe developmental delay. Some MCT8 deficient patients are not as severely affected than others due to residual thyroid hormone (TH) transport. Previously, we hypothesized that these patients’ mutations destabilize the MCT8 protein, which consequently will be sent for degradation. We have already demonstrated that the chemical chaperone sodium phenylbutyrate (NaPB) rescues the function of these mutants by stabilizing their protein expression in an overexpressing cell system. Here we expand our previous work and used human iPSC-derived brain microvascular endothelial-like cells (iBMECs) as a model. We could show that NaPB rescues decreased mutant MCT8 expression and restores transport function. Furthermore, we identified MCT10 as another TH transporter that contributes to T3 uptake. The decrease in mutant protein expression could be explained by the activation of components of the unfolded protein response (UPR) machinery. Increased expression after NaPB treatment is a consequence of UPR attenuation and the stabilization of MCT8 mRNA. In conclusion, we demonstrate that NaPB is suitable to stabilize pathogenic missense mutations and activate transport function in a human-derived cell model opening the possibility of repurposing the FDA-approved drug NaPB for MCT8 deficiency.
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