Mechanisms of disease: psychomotor retardation and high T-3 levels caused by mutations in monocarboxylate transporter 8

The actions and the metabolism of thyroid hormone are intracellular events that require the transport of iodothyronines across the plasma membrane. It is increasingly clear that this process does not occur by simple diffusion, but is facilitated by transport proteins. Only recently have iodothyronine transporters been identified at the molecular level, of which organic anion transporting polypeptide 1C1 and monocarboxylate transporter 8 (MCT8) deserve special mention, because of their high activity and specificity for iodothyronines. Organic anion transporting polypeptide 1C1 is almost exclusively expressed in brain capillaries, and may be crucial for the transport of the prohormone T-4 across the blood-brain barrier. MCT8 is also expressed in the brain-in particular, in neurons-but also in other tissues. MCT8 seems to be especially important for the uptake of active hormone T-3 into neurons, which is essential for optimal brain development. T-3 is produced from T-4 by type 2 deiodinase in neighboring astrocytes. Neurons express type 3 deiodinase, the enzyme that terminates T-3 activity. The SLC16A2 (formerly MCT8) gene is located on chromosome Xq13.2 and has recently been associated with a syndrome combining severe, X-linked, psychomotor retardation and high serum T-3 levels. In over 20 families, where affected males have developed this syndrome, several mutations in MCT8 have been identified. The disease mechanism is thought to involve a defect in the neuronal entry of T-3 and, therefore, in the action and metabolism of T-3 in these cells. This defect results in impaired neurological development and a decrease in T-3 clearance.