In 2022, the activation mechanism of TSH receptor (TSHR) by TSH and autoantibodies was demonstrated, monocarboxylate transporter 8 (MCT8) deficiency was corrected with gene therapy in mice and mutant thyroid hormone receptor α (TRα) was activated with a synthetic ligand. These results offer translational perspectives for patients with common and rare diseases affecting these proteins.
Key advances
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The structure of full-length TSHR was resolved by cryo-EM in complex with TSH or antibodies, providing a model for TSHR activation; TSH binding stabilizes the extracellular domain of TSHR in an upright position away from the cell membrane, which activates the receptor1,2,3.
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Adeno-associated virus-mediated expression of the TH transporter MCT8 partially improves the neurological phenotype of MCT8 deficiency in mice; brain TH content, TH target gene expression and locomotor function improved after a single MCT8-virus injection and even persisted into adulthood when juvenile mice were treated6,7.
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A synthetic TH receptor α (TRα) ligand relieves transcriptional repression of mutant TRα and rescues the phenotype of resistance to THα in a zebrafish model10.
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References
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Sundaram, S. M. et al. Gene therapy targeting the blood-brain barrier improves neurological symptoms in a model of genetic MCT8 deficiency. Brain https://doi.org/10.1093/brain/awac243 (2022).
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Moeller, L.C. Translational perspectives from TSHR, MCT8 and TRα research. Nat Rev Endocrinol 19, 74–75 (2023). https://doi.org/10.1038/s41574-022-00785-1
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DOI: https://doi.org/10.1038/s41574-022-00785-1
