Molecular aspects of thyroid hormone transporters, including MCT8, MCT10, and OATPs, and the effects of genetic variation in these transporters

Abstract

Thyroid hormone is a pleiotropic hormone with widespread biological actions. For instance, adequate levels of thyroid hormone are critical for the development of different tissues such as the central nervous system, but are also essential for the regulation of metabolic processes throughout life. The biological activity of thyroid hormone depends not only on serum thyroid hormone levels, but is also regulated at the tissue level by the expression and activity of deiodinases, which activate thyroid hormone or mediate its degradation. In addition, thyroid hormone transporters are necessary for the uptake of thyroid hormone into target tissues. With the discovery of monocarboxylate transporter 8 (MCT8) as a specific thyroid hormone transporter and the finding that mutations in this transporter lead to a syndrome of severe psychomotor retardation and elevated serum 3,3 0 ,5-tri-iodothyronine levels known as the Allan-Herndon-Dudley syndrome, the interest in this area of research has greatly increased. In this review, we will focus on the molecular aspects of thyroid hormone transporters, including MCT8, MCT10, organic anion transporting polypeptides, and the effects of genetic variation in these transporters.

A child with a deletion in the monocarboxylate transporter 8 gene: 7-year follow-up and effects of thyroid hormone treatment

“…These observations may reflect variability in MCT8 expression at different tissues or a role of alternative T 3 transport systems. Unfortunately, these transporters could not mediate any motor or cognitive improvement in our patient, even in response to high doses of LT 3 . An early administration of thyroid hormones during infancy, especially in AHDS patients with partial activity of the MCT8, should be examined (7).…”

“…There were no other signs compatible with hyperthyroidism, as body weight was increased during therapy, and no excessive sweating or hyperactivity was observed. Along with an increment in serum T 3 levels, FT 4 , and TSH levels were progressively decreased, liver transaminases were mildly increased, and sex hormone-binding globulin (SHBG) was remarkably increased in response to the elevation in LT 3 doses. Yet, this intervention failed to induce any change in the patient's motor or cognitive functions.…”

“…AHDS is known to be caused by mutations in the SLC16A2 gene that encodes the monocarboxylate transporter 8 (MCT8) (2). This transporter is expressed in numerous human tissues including brain, heart, placenta, lung, kidney, skeletal muscle, and liver (3)(4)(5) and facilitates cellular T 3 uptake (6,7). Subsequently, MCT8 mutations result in a diminished intracellular T 3 concentration (8,9).…”

“…We describe here the genetic study and a follow-up of a child with AHDS who was treated with LT 4 for about 6.5 years and with low-and high-dose liothyronine (LT 3 ) for a short period of time. The treatment with high-dose LT 3 was intended to overcome the T 3 uptake inhibition at the CNS through alternative transport routes.…”

“…The treatment with high-dose LT 3 was intended to overcome the T 3 uptake inhibition at the CNS through alternative transport routes. Such routes could involve MCT10 and the organic anion transporting polypeptide 1A2 (OATP1A2), which facilitate T 3 uptake similar to MCT8 (3,21).…”