2.A.1.13.10
MCT8 (SLC16a2) homodimeric monocarboxylate thyroid hormone transporter 8 of 613 or 539 aas and 12 TMSs (Visser et al. 2009; Arjona et al., 2011).  It is the X-linked mental retardation Allan-Herndon-Dudley syndrome (AHDS) (a severe psychomotor retardation syndrome) protein (Schweizer and Köhrle 2012; Boccone et al. 2010; Johannes et al. 2016). Lack of MCT8 function produces serious neurological disturbances, most likely due to impaired transport of thyroid hormones across brain barriers during development, resulting in severe brain hypothyroidism (Grijota-Martínez et al. 2020). Arg residues important for function have been identified (Groeneweg et al. 2013).  Thyroid hormone (TH) transporters in the brain and across the blood brain barrier have been reviewed (Wirth et al. 2014; Bernal et al. 2015). The product facilitates both TH uptake and efflux across the cell membrane. The disease goes together with low serum T4 and high T3 levels. The mechanisms underlying MCT8-deficient brain development in various animal models including humans has been reviewed (Vancamp and Darras 2017). Together with OATP1C1 (TC# 2.A.60.1.15), MCT8 controls skeletal muscle regeneration (Mayerl et al. 2018).  Deafness and loss of cochlear hair cells occurs in the absence of thyroid hormone transporters, Slc16a2 (Mct8) and Slc16a10 (Mct10) (Sharlin et al. 2018). Stable levels of MCT8 protein in endothelial cells of the blood-brain barrier, choroid plexus epithelial cells and tanycytes during postnatal development has been demonstrated (Wilpert et al. 2020). Oligomerization involves noncovalent interactions between the N-terminal halves of MCT8 proteins (Groeneweg et al. 2020). Genetic variants in MCT8, cause intellectual and motor disability and abnormal serum thyroid function tests, known as MCT8 deficiency (van Geest et al. 2020). Shaji 2021 identified natural inhibitors against MCT8. Emodin exhibited the best binding energy of -8.6 kcal/mol followed by helenaquinol, cercosporamide and resveratrol. Emodin and helenaquinol exhibit high binding energy. Cercosporamide and resveratrol exhibited higher binding energy than triac and desipramine and showed the binding energy similar to silychristin. Thus, these compounds could be promising candidates for further evaluation for AHDS prevention. MCT8 deficiency induces severe X-linked psychomotor retardation (Iwayama et al. 2021). It is common and severe in homozygous males (one X chromosome) but mild in heterozygous females (XX) (Dumitrescu et al. 2004). Thyroid normone transporters MCT8 and OATP1C1 are expressed in pyramidal neurons and interneurons in the adult motor cortex of human and macaque brains (Wang et al. 2023). Thyroid hormone transporters MCT8 and OATP1C1 are expressed in projection neurons and interneurons of basal ganglia and motor thalamus in adult human brains (Wang et al. 2023). MCT8 plays a vital role in maintaining brain thyroid hormone homeostasis. This transporter is expressed at the brain barriers, as the blood-brain barrier (BBB), and in neural cells, being the sole known thyroid hormone-specific transporter to date. Inactivating mutations in the MCT8 gene cause the Allan-Herndon-Dudley Syndrome (AHDS) or MCT8 deficiency, a rare X-linked disease characterized by delayed neurodevelopment and severe psychomotor disorders as well as BBB leakage (Guillén-Yunta et al. 2023).

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