Mechanisms of Disease: psychomotor retardation and high T3 levels caused by mutations in monocarboxylate transporter 8

Abstract

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 T4 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 T3 into neurons, which is essential for optimal brain development. T3 is produced from T4 by type 2 deiodinase in neighboring astrocytes. Neurons express type 3 deiodinase, the enzyme that terminates T3 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 T3 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 T3 and, therefore, in the action and metabolism of T3 in these cells. This defect results in impaired neurological development and a decrease in T3 clearance.

Thyroid hormone action during brain development: More questions than answers

“…All patients suffered from a unique syndrome consisting of a severe form of psychomotor retardation in combination with abnormal serum thyroid hormone levels (Friesema et al, 2006). Serum T3 levels were found to be highly elevated whereas T4 concentrations were rather low.…”

Thyroid hormones and fetal neurological development

“…In humans, the absence of the MCT8 transporter (the Allan-Herndon-Dudley syndrome) results in X-linked moderate to severe mental retardation and muscle hypotonia and hypoplasia (Dumitrescu et al 2004, Friesema et al 2004, Schwartz et al 2005. Raised serum T 3 concentrations and low T 4 levels are present, but TSH levels are normal suggesting a role for MCT8 in pituitary thyroid hormone uptake (Friesema et al 2006). Patients also display altered and delayed maturation of myelination (Namba et al 2008).…”

MCT8 mutation analysis and identification of the first female with Allan–Herndon–Dudley syndrome due to loss of MCT8 expression

“…7 Clinical variability within and between MCT8 mutation families has been reported. 8 The reported MCT8 mutation female carriers showed normal growth and psychomotor development, they had normal facial appearance, and they did not present with neurological symptoms. This is most likely explained by normal random X-inactivation or favorable nonrandom X-inactivation.…”