Thyroid Hormone Transporters

Abstract

Thyroid hormone transporters at the plasma membrane govern intracellular bioavailability of thyroid hormone. Monocarboxylate transporter (MCT) 8 and MCT10, organic anion transporting polypeptide (OATP) 1C1, and SLC17A4 are currently known as transporters displaying the highest specificity toward thyroid hormones. Structure-function studies using homology modeling and mutational screens have led to better understanding of the molecular basis of thyroid hormone transport. Mutations in MCT8 and in OATP1C1 have been associated with clinical disorders. Different animal models have provided insight into the functional role of thyroid hormone transporters, in particular MCT8. Different treatment strategies for MCT8 deficiency have been explored, of which thyroid hormone analogue therapy is currently applied in patients. Future studies may reveal the identity of as-yet-undiscovered thyroid hormone transporters. Complementary studies employing animal and human models will provide further insight into the role of transporters in health and disease.

The Protein Translocation Defect of MCT8L291R Is Rescued by Sodium Phenylbutyrate

“…The Triac Trial I successfully reported the reduction of the thyrotoxic effect of high T 3 and the safety of Triac administration in MCT8-deficient patients [15]. The Triac Trial II (NCT02396459) is going to elucidate the effect of Triac on neurocognitive development [8]. Sobetirome and its prodrug Sob-AM2 are additional thyromimetic agents that do not depend on MCT8 for cellular entry.…”

“…Mutations in MCT8 lead to severe developmental and neurocognitive impairments [4, 5]. Its expression in several areas of the developing human brain [6, 7] and the symptoms of intellectual and motor disabilities found in MCT8-deficient patients suggest a pivotal role of MCT8 for proper development of the brain [nicely summarized in 8].…”

“…The brain phenotype of these mice could be rescued by administration of the T 3 metabolite 3,3′,5-triiodothyroacetic acid (Triac) [14]. Triac is a T 3 receptor agonist and is currently under investigation as a possible treatment option for MCT8-deficient patients [8, 15].…”

“…Groeneweg et al [8] reported about at least 320 individuals in 132 families with MCT8 deficiency. Among MCT8 mutations, there are 48 mutations published that comprise insertion, deletions, or substitution of single amino acids [8].…”

“…Groeneweg et al [8] reported about at least 320 individuals in 132 families with MCT8 deficiency. Among MCT8 mutations, there are 48 mutations published that comprise insertion, deletions, or substitution of single amino acids [8]. We and others have already demonstrated that NaPB is able to stabilize and rescue the protein expression and function of seven of these MCT8 mutants in vitro [19-21].…”