Psychomotor Retardation Caused by Mutations in MCT8: pathogenesis and therapy

Abstract

Thyroid hormone (TH) is essential during childhood for proper brain and physical development (e.g. bone), and in adulthood for metabolic regulation of essentially every tissue in the human body. The thyroid produces mostly the pro-hormone T4 (3,3’,5,5’-tetraiodothyronine, thyroxine) and a small amount of the active hormone T3 (3,3’,5-triiodothyronine). Both T3 and T4 are produced in the thyroid gland, but T4 is primarily produced. Most T3 is produced in peripheral tissues by the conversion of T4 to T3 by the type 1 (D1) and type 2 (D2) deiodinases (1). A third deiodinase (D3) catalyzes the inactivation of T4 to rT3 (3,3’,5’-triiodothyronine) and of T3 to 3,3’-T2 (3,3’-diiodothyronine) (Fig 1). Serum TH levels are carefully regulated by the hypothalamus-pituitary-thyroid axis (2). Hypothalamic thyrotropin releasing hormone (TRH) stimulates the synthesis and secretion of thyroid stimulating hormone (TSH) in the anterior pituitary (3) which in turn stimulates the thyroid gland to produce and secrete TH (4). The HPT axis is kept in balance by the negative feed-back of TH at the level of the hypothalamus and pituitary. Deiodination is an intracellular process as is TH action, which is principally exerted in the nucleus where T3 modifies transcription of target genes (5). The nuclear actions of T3 are dependent on two main factors: the presence of functional T3 receptors and the intracellular T3 levels. T3 receptors come in different subtypes (TRα1, TRβ1, TRβ2) derived from the THRA and THRB genes. The intracellular TH levels are controlled importantly by TH transporters that mediate transport of TH across the plasma membrane as well as by the opposing activities of in particular D2 and D3. The general focus of this thesis is on TH transporters.