Tissue-specific effects of mutations in the thyroid hormone transporter MCT8

Abstract

T hyroid hormone (TH) is important for the development of different tissues, in particular the brain, as well as for the regulation of the metabolic activities of the tissues and thermogenesis throughout life. Most TH actions are initiated by binding of the active hormone 3,3',5-triiodothyronine (T3) to its nuclear receptor. This induces an alteration in proteins associated with the transcription initiation complex, resulting in the stimulation or suppression of the expression of TH responsive genes.The biological activity of TH is thus determined by the intracellular T3 concentration, which is only indirectly dependent on the function of the thyroid gland which secretes predominantly the prohormone thyroxine (3,3',5,5'-tetraiodothyronine, T4). In many target tissues, T3 availability is regulated in a paracrine manner, where T3 supply to target cells is derived from T4 to T3 conversion in neighbouring cells. Brain and cochlea are examples of tissues with paracrine regulation of TH action. In other tissues, such as the pituitary and brown adipose tissue (BAT), T3 may be produced from T4 directly in its target cells, representing an autocrine mechanism of TH action (Figure 1). In yet other tissues such as the liver and the kidneys, intracellular T3 is in rapid exchange with circulating T3. This could be regarded as an endocrine action of T3, although it is still largely derived from peripheral conversion of T4 even in these same tissues.In contrast to the activation of T4 by enzymatic outer ring deiodination (ORD) to T3, TH is inactivated by inner ring deiodination (IRD), which converts T4 to 3,3',5'-triiodothyronine (reverse T3, rT3) and T3 to 3,3'-diiodothyronine (T2) (1). Three iodothyronine deiodinases (D1-3) are involved in these different deiodination reactions (1). D1 is expressed in liver, kidneys and thyroid and has both ORD and IRD activity. It is thought to contribute importantly to production of serum T3, in particular in eu-and hyperthyroid conditions. D2 has only ORD activity and is expressed in brain, pituitary, BAT, thyroid and skeletal muscle. It is essential for local production of T3 in brain, pituitary and BAT, but the enzyme in thyroid and muscle may also be an important site for production of serum T3 in eu-and hypothyroid subjects. D3 is highly expressed in different fetal tissues, placenta and pregnant uterus, and also in adult brain and skin. It has only IRD activity and thus catalyzes the inactivation of TH. Together with D2, D3 has a crucial role in the region-specific and time-dependent regulation of T3 in the developing brain. The deiodinases are homologous selenoprotein embedded in the membrane of the endoplasmic reticulum or the plasma membrane, such that the active sites are located in the cytoplasm (1).TH metabolism and action are intracellular processes that require transport of iodothyronines across the cell membrane. This does not take place by passive diffusion but requires the involvement of specific transporters (2). A number of multi--specific transporters have been identifi...

Psychomotor Retardation Caused by a Defective Thyroid Hormone Transporter: Report of Two Families with Different <b><i>MCT8</i></b> Mutations

“…Administration of LT4 caused a decrease in serum TSH, but interestingly also a decrease in serum T3. This was explained by the strong negative correlation of TSH with FT4 and positive correlation with T3, which supports the hypothesis that thyroidal T3 secretion contributes to elevated serum T3 levels in MCT8 patients [28]. Zung et al [26] reported an 8-year-old boy with a deletion of exons 2-6 of MCT8 , who was treated with LT4 for 6.5 years, followed by LT4+LT3 therapy for 6 months.…”

“…In AHDS patients, T3 levels may be low in some tissues, such as the brain, but high in other tissue, such as liver and skeletal muscle, depending on the importance of MCT8 in mediating T3 uptake and/or efflux at these different sites [28]. Despite the normal birth weight in patients, inadequate weight gain and generalized muscle loss are seen probably as a result of increased metabolic rate associated with a hyperthyroid state of liver, skeletal muscle and fat tissue.…”

“…However, no significant clinical improvement was seen in these patients. Actually, this treatment may result in an increased T3 exposure of tissue which does not need MCT8 for TH uptake, with a deterioration of symptoms such as muscle wasting [28]. Normalization of the T3 and T4 levels may bring benefits as abnormal serum T3 and T4 levels play a role in the clinical picture.…”

Transport of thyroid hormones via the choroid plexus into the brain: the roles of transthyretin and thyroid hormone transmembrane transporters

“…Intriguingly, there exists dramatic species-specificity in TH transmembrane transporters deficiency phenotypes. For example, human males with MCT8 mutations present with mental retardation (IQ <40), speech deficits and severe neurological abnormalities (known as the Allan-Herndon-Dudley syndrome), whereas MCT8 null mice are without an overt neurological phenotype (Kersseboom and Visser, 2011). The discovery of the suite of TH transmembrane transporters, particularly in the choroid plexus, was important in understanding how TTR null mice were without an overt phenotype.…”

Hypothyroidism: diagnosis and screening, genetic influences, and treatment options

“…For this reason, many patients treated with LT 4 have experienced no benefit, and may in fact experience detrimental effects. For example, an increased T 3 exposure to tissues that can perform MCT8-independent T 3 uptake, like the heart, may suffer from induced or aggravate tachycardia (75).…”