Papers

The objective of the study was to evaluate the effect and efficacy of DITPA in children with MCT8 deficiency.

Monocarboxylate transporter 8 (MCT8) deficiency is an X-linked disorder resulting from an impairment of the transcellular transportation of thyroid hormones. Within the central nervous system thyroid hormone transport is normally mediated by MCT8. Patients are described as affected by a static or slowly progressive clinical picture which consists of variable degrees of mental retardation, hypotonia, spasticity, ataxia and involuntary movements, occasionally paroxysmal. The authors describe the clinical and neuroradiological picture of 3 males patients with marked delayed brain myelination and in which the clinical picture was dominated by early onset nonparoxismal extrapyramidal symptoms. In one subject a novel mutation is described.

A partial deletion of the MCT8 gene (comprising five of six exons) was detected, confirming the suspected AHDS. MCT8 dysfunction was associated with partial resistance to T3 at the hypothalamus and pituitary level, with normal responsiveness at the peripheral organs (liver and cardiovascular system). Thyroid hormone administration had no beneficial effect on the neurological status of the patient.

Carmen Grijota-Martínez, Diego Díez, Gabriella Morreale de Escobar, Juan Bernal, and Beatriz Morte Abstract:  Mutations of the monocarboxylate transporter 8 gene (MCT8, SLC16A2) cause the Allan-Herndon- Dudley syndrome, an X-linked syndrome of severe intellectual deficit and neurological impairment. Mct8 transports thyroid hormones (T4 and T3), and the Allan-Herndon-Dudley syndrome is likely caused by lack of […]

Thyroid 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.

Retinoic acid (RA) and thyroid hormone are critical for differentiation and organogenesis in the embryo. Mct8 (monocarboxylate transporter 8), expressed predominantly in the brain and placenta, mediates thyroid hormone uptake from the circulation and is required for normal neural development. RA induces differentiation of F9 mouse teratocarcinoma cells toward neurons as well as extraembryonal endoderm. We hypothesized that Mct8 is functionally expressed in F9 cells and induced by RA. All-trans-RA (tRA) and other RA receptor (RAR) agonists dramatically (>300-fold) induced Mct8. tRA treatment significantly increased uptake of triiodothyronine and thyroxine (4.1- and 4.3-fold, respectively), which was abolished by a selective Mct8 inhibitor, bromosulfophthalein. Sequence inspection of the Mct8 promoter region and 5-rapid amplification of cDNA ends PCR analysis in F9 cells identified 11 transcription start sites and a proximal Sp1 site but no TATA box.

The mechanism of thyroid hormone (TH) secretion from the thyroid gland into blood is unknown. Humans and mice deficient in monocarboxylate transporter 8 (MCT8) have low serum thyroxine (T4) levels that cannot be fully explained by increased deiodination. Here, we have shown that Mct8 is localized at the basolateral membrane of thyrocytes and that the serum TH concentration is reduced in Mct8-KO mice early after being taken off a treatment that almost completely depleted the thyroid gland of TH. Thyroid glands in Mct8-KO mice contained more non-thyroglobulin-associated T4 and triiodothyronine than did those in wild-type mice, independent of deiodination. In addition, depletion of thyroidal TH content was slower during iodine deficiency.

Monocarboxylate transporter 8 (MCT8, SLC16A2) is a thyroid hormone (TH) transmembrane transport protein mutated in Allan-Herndon-Dudley syndrome, a severe Xlinked psychomotor retardation. The neurological and endocrine phenotypes of patients deficient in MCT8 function underscore the physiological significance of carriermediated TH transmembrane transport. MCT8 belongs to the major facilitator superfamily of 12 transmembrane spanning proteins and mediates energy-independent bidirectional transport of iodothyronines across the plasma membrane. Structural information is lacking for all TH transmembrane transporters. In order to gain insight into structure-function relations in TH transport, we chose human MCT8 as paradigm. We systematically performed conventional and liquid chromatographytandem mass spectrometry-based uptake measurements into MCT8-transfected cells using a large number of compounds structurally related to iodothyronines.

Transport of thyroid hormones across the plasma membrane is required for binding to their nuclear receptors. Monocarboxylate transporter 8 (MCT8) is a plasma membrane thyroid hormone transport protein, which has recently gained much attention, since mutations in MCT8 are associated with severe mental retardation in patients afflicted with the Allan- Herndon-Dudley syndrome. MCT8 is expressed along the blood-brain-barrier and on central neurons. We have found that desipramine (DMI), a tricyclic antidepressant, acts as an inhibitor of thyroid hormone transport by MCT8. Uptake of 3,5,3’-triiodo-L-thyronine (T3) into primary cortical neurons could be blocked with desipramine as well as with the known, but unspecific, inhibitor bromosulphtalein (BSP). T3 uptake by neurons derived from Mct8- deficient cells was not further decreased by DMI. In a heterologous expression system, both human MCT8 and its close homolog, MCT10, were sensitive to inhibition by DMI.

Thyroid hormone (TH) induces the dramatic morphological and physiological changes that together comprise amphibian metamorphosis. TH-responsive tissues vary widely with developmental timing of TH-induced changes. How larval tadpole tissues are able to employ distinct metamorphic programs in a developmental stage- and TH-dependent manner is still unknown. Recently, several proteins capable of transporting TH have been identified. TH action and metabolism occurs primarily intracellularly, high- lighting the importance of TH transporters. We examined the hypothesis that TH transporter expression and tissue distribution play an important role in mediating TH-induced metamorphic events.