Endocrine Abstracts

Thyroid hormone is essential for the metabolic function of all tissues throughout life and for the development of different organs, notably the brain. Although the thyroid gland mainly secretes T4, most actions of thyroid hormone are initiated by binding of T3 to its nuclear receptor. The biological activity of thyroid hormone in target cells is determined by the intracellular T3 concentration which depends on the circulating levels of T3 and its precursor T4, the activity of the iodothyronine deiodinases catalyzing the conversion of T4 to T3 (D1,2) or the degradation of T3 (D3), and the presence of transporters in the plasma membrane, facilitating the cellular in- and/or efflux of T4 and T3. The deiodinases are membrane proteins with their active sites located in the cytoplasm. Therefore, not only the action but also the metabolism of thyroid hormone require the cellular uptake of the hormone.

Recently, two important thyroid hormone transporters have been identified: OATP1C1 is specific for T4 and rT3, and is almost exclusively expressed in brain, in particular in capillaries. It is probably essential for transport of T4 across the blood-brain barrier. Human MCT8 has been identified as an active thyroid hormone transporter with preference for T3 that is expressed in a variety of tissues, including the brain. It is probably importantly involved in T3 uptake in neurons, the primary targets of thyroid hormone action during brain development. The MCT8 gene is located on the X chromosome. We have identified mutations in MCT8 in six unrelated boys with severe psychomotor retardation and strongly elevated serum T3 levels. These mutations result in the inhibition of T3 supply to neurons, leading to a defect in brain development and a decreased T3 clearance by neuronal D3.