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

2011 ◽  
Vol 165 (5) ◽  
pp. 823-830 ◽  
Author(s):  
Amnon Zung ◽  
Theo J Visser ◽  
André G Uitterlinden ◽  
Fernando Rivadeneira ◽  
Edith C H Friesema
Keyword(s):  
Thyroid Hormone ◽  
Snp Array ◽  
Hormone Treatment ◽  
Neurological Status ◽  
Psychomotor Retardation ◽  
Monocarboxylate Transporter ◽  
High Dose ◽  
Hormone Administration ◽  
Hormone Analogs

ObjectiveThe monocarboxylate transporter 8 (MCT8; SLC16A2) has a pivotal role in neuronal triiodothyronine (T3) uptake. Mutations of this transporter determine a distinct X-linked psychomotor retardation syndrome (Allan–Herndon–Dudley syndrome (AHDS)) that is attributed to disturbed thyroid hormone levels, especially elevated T3 levels. We describe the genetic analysis of the MCT8 gene in a patient suspected for AHDS and the clinical and endocrine effects of L-thyroxine (LT4) or liothyronine (LT3) treatment intending to overcome the T3 uptake resistance through alternative transporters.MethodsThe six exons of the MCT8 gene were amplified individually by PCR. As multiple exons were missing, the length of the X-chromosomal deletion was determined by a dense SNP array, followed by PCR-based fine mapping to define the exact borders of the deleted segment. The clinical and endocrine data of the patient during 6.5 years of LT4 treatment and two periods (3 months each) of low- and high-dose LT3 were evaluated.ResultsA 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.ConclusionWe identified a 70 kb deletion encompassing exons 2–6 of the MCT8 gene in our AHDS patient. Both LT4 and LT3 administration had no therapeutic effect. Alternatively, treatment of AHDS patients with thyroid hormone analogs should be considered.

scholarly journals Minireview: Thyroid Hormone Transporters: The Knowns and the Unknowns

2011 ◽  
Vol 25 (1) ◽  
pp. 1-14 ◽  
Author(s):  
W. Edward Visser ◽  
Edith C. H. Friesema ◽  
Theo J. Visser
Keyword(s):  
Thyroid Hormone ◽  
Organic Anion ◽  
Psychomotor Retardation ◽  
Cellular Level ◽  
Monocarboxylate Transporter ◽  
Causative Role ◽  
Organic Anion Transporting Polypeptide ◽  
Neurological Abnormalities ◽  
Knockout Animals

The effects of thyroid hormone (TH) on development and metabolism are exerted at the cellular level. Metabolism and action of TH take place intracellularly, which require transport of the hormone across the plasma membrane. This process is mediated by TH transporter proteins. Many TH transporters have been identified at the molecular level, although a few are classified as specific TH transporters, including monocarboxylate transporter (MCT)8, MCT10, and organic anion-transporting polypeptide 1C1. The importance of TH transporters for physiology has been illustrated dramatically by the causative role of MCT8 mutations in males with psychomotor retardation and abnormal serum TH concentrations. Although Mct8 knockout animals have provided insight in the mechanisms underlying parts of the endocrine phenotype, they lack obvious neurological abnormalities. Thus, the pathogenesis of the neurological abnormalities in males with MCT8 mutations is not fully understood. The prospects of identifying other transporters and transporter-based syndromes promise an exciting future in the TH transporter field.

scholarly journals Differential modulation of expression of the two acylphosphatase isoenzymes by thyroid hormone

1995 ◽  
Vol 311 (2) ◽  
pp. 567-573 ◽  
Author(s):  
P Chiarugi ◽  
G Raugei ◽  
R Marzocchini ◽  
T Fiaschi ◽  
C Ciccarelli ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Thyroid Hormone ◽  
State Level ◽  
K562 Cells ◽  
Hormone Treatment ◽  
Differential Regulation ◽  
Rapid Decrease ◽  
Differential Modulation ◽  
Hormone Administration ◽  
Specific Mrna

The modulation of expression of the skeletal muscle and erythrocyte acylphosphatase isoenzymes by thyroid hormone has been investigated. Our results indicate a differential regulation of the two enzymic isoforms by tri-iodothyronine (T3) in K562 cells in culture: an increase in the specific mRNA during T3-stimulation is shown only for the skeletal muscle isoenzyme. A fast and transient T3 induction of the accumulation of the specific mRNA can be observed, reaching a maximum 8 h after hormone treatment and then rapidly decreasing almost to the steady-state level after 24 h. A nuclear run-on assay was performed to explore the mechanisms of this regulation. These studies indicate that T3 induction of skeletal muscle acylphosphatase mRNA is due, at least in part, to a fast and transient increase in the rate of gene transcription, within 4 h after hormone administration. A very rapid decrease is then observed within a further 2 h. T3-dependent accumulation of the mRNA for the skeletal muscle acylphosphatase requires ongoing protein synthesis, as confirmed by inhibition with cycloheximide or puromycin. These findings indicate that the transcriptional regulation of the gene may be indirect.

scholarly journals Tissue Thyroid Hormone Levels in Critical Illness

2005 ◽  
Vol 90 (12) ◽  
pp. 6498-6507 ◽  
Author(s):  
Robin P. Peeters ◽  
Serge van der Geyten ◽  
Pieter J. Wouters ◽  
Veerle M. Darras ◽  
Hans van Toor ◽  
...  
Keyword(s):  
Critical Illness ◽  
Thyroid Hormone ◽  
Hormone Treatment ◽  
Monocarboxylate Transporter ◽  
Total Serum ◽  
Tissue Specific ◽  
Hormone Levels ◽  
Serum T3 ◽  
Serum Thyroid Hormone ◽  
Thyroid Hormone Levels

Context: Pronounced alterations in serum thyroid hormone levels occur during critical illness. T3 decreases and rT3 increases, the magnitudes of which are related to the severity of disease. It is unclear whether these changes are associated with decreased tissue T3 concentrations and, thus, reduced thyroid hormone bioactivity. Patients and Study Questions: We therefore investigated, in 79 patients who died after intensive care and who did or did not receive thyroid hormone treatment, whether total serum thyroid hormone levels correspond to tissue levels in liver and muscle. Furthermore, we investigated the relationship between tissue thyroid hormone levels, deiodinase activities, and monocarboxylate transporter 8 expression. Results: Tissue iodothyronine levels were positively correlated with serum levels, indicating that the decrease in serum T3 during illness is associated with decreased levels of tissue T3. Higher serum T3 levels in patients who received thyroid hormone treatment were accompanied by higher levels of liver and muscle T3, with evidence for tissue-specific regulation. Tissue rT3 and the T3/rT3 ratio were correlated with tissue deiodinase activities. Monocarboxylate transporter 8 expression was not related to the ratio of the serum over tissue concentration of the different iodothyronines. Conclusion: Our results suggest that, in addition to changes in the hypothalamus-pituitary-thyroid axis, tissue-specific mechanisms are involved in the reduced supply of bioactive thyroid hormone in critical illness.

scholarly journals Evidence for a Homodimeric Structure of Human Monocarboxylate Transporter 8

Endocrinology ◽  
2009 ◽  
Vol 150 (11) ◽  
pp. 5163-5170 ◽  
Author(s):  
W. Edward Visser ◽  
Nancy J. Philp ◽  
Thamar B. van Dijk ◽  
Wim Klootwijk ◽  
Edith C. H. Friesema ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Psychomotor Retardation ◽  
Monocarboxylate Transporter ◽  
Membrane Association ◽  
Transport Function ◽  
Wild Type ◽  
Transfected Cells ◽  
Physiological Relevance ◽  
Dimerization Process

The human monocarboxylate transporter 8 (hMCT8) protein mediates transport of thyroid hormone across the plasma membrane. Association of hMCT8 mutations with severe psychomotor retardation and disturbed thyroid hormone levels has established its physiological relevance, but little is still known about the basic properties of hMCT8. In this study we present evidence that hMCT8 does not form heterodimers with the ancillary proteins basigin, embigin, or neuroplastin, unlike other MCTs. In contrast, it is suggested that MCT8 exists as monomer and homodimer in transiently and stably transfected cells. Apparently hMCT8 forms stable dimers because the complex is resistant to denaturing conditions and dithiothreitol. Cotransfection of wild-type hMCT8 with a mutant lacking amino acids 267–360 resulted in formation of homo-and heterodimers of the variants, indicating that transmembrane domains 4–6 are not involved in the dimerization process. Furthermore, we explored the structural and functional role of the 10 Cys residues in hMCT8. All possible Cys>Ala mutants did not behave differently from wild-type hMCT8 in protein expression, cross-linking experiments with HgCl2 and transport function. Our findings indicate that individual Cys residues are not important for the function of hMCT8 or suggest that hMCT8 has other yet-undiscovered functions in which cysteines play an essential role.

scholarly journals Histidines in Potential Substrate Recognition Sites Affect Thyroid Hormone Transport by Monocarboxylate Transporter 8 (MCT8)

Endocrinology ◽  
2013 ◽  
Vol 154 (7) ◽  
pp. 2553-2561 ◽  
Author(s):  
Doreen Braun ◽  
Iva Lelios ◽  
Gerd Krause ◽  
Ulrich Schweizer
Keyword(s):  
Thyroid Hormone ◽  
Ring Structure ◽  
Psychomotor Retardation ◽  
Major Facilitator Superfamily ◽  
Site Directed Mutagenesis ◽  
Monocarboxylate Transporter ◽  
Transport Channel ◽  
Hormone Transport ◽  
Bonding Properties ◽  
Major Facilitator

Abstract Mutations in monocarboxylate transporter 8 (MCT8; SLC16A2) cause the Allan-Herndon-Dudley syndrome, a severe X-linked psychomotor retardation syndrome. MCT8 belongs to the major facilitator superfamily of 12 transmembrane-spanning proteins and transports thyroid hormones across the blood-brain barrier and into neurons. How MCT8 distinguishes thyroid hormone substrates from structurally closely related compounds is not known. The goal of this study was to identify critical amino acids along the transport channel cavity, which participate in thyroid hormone recognition. The fact that T3 is bound between a His-Arg clamp in the crystal structure of the T3 receptor/T3 complex prompted us to investigate whether such a motif might potentially be relevant for T3 recognition in MCT8. We therefore replaced candidate histidines and arginines by site-directed mutagenesis and performed activity assays in MDCK-1 cells and Xenopus oocytes. Histidines were replaced by alanine, phenylalanine, and glutamine to probe for molecular properties like aromatic ring structure and H-bonding properties. It was found that some mutations in His192 and His415 significantly changed substrate transport kinetics. Arg301 at the intracellular end of the substrate channel is at an ideal distance to His415 to participate in a His-Arg clamp and mutation to alanine-abrogated hormone transport. Molecular modeling demonstrates a perfect fit of T3 poised into the substrate channel between His415 and Arg301 and observing the same geometry as in the T3 receptor.

Hashimoto's Encephalopathy

2020 ◽  
pp. 126-140
Keyword(s):  
Thyroid Hormone ◽  
Oral Prednisone ◽  
Hormone Treatment ◽  
High Dose ◽  
Thyroid Antibodies ◽  
Depression And Anxiety ◽  
Hashimoto’S Encephalopathy ◽  
Methyl Prednisolone ◽  
Neuro Inflammation

Hashimoto's encephalopathy is a relapsing encephalopathy occurring in association with Hashimoto's thyroiditis (HT) with high titers of anti-thyroid antibodies. The mechanism of pathogenesis is unknown. Auto-antibodies to α-enolase have been found to be associated with Hashimoto's encephalopathy. Recently, the crucial role of neuro-inflammation in the development of psychological disorders including depression and anxiety has received more attention. Because the majority of patients with Hashimoto's encephalopathy respond to steroids or immuno-suppressant treatment, this condition is now also referred to as “steroid-responsive encephalopathy.” Initial treatment is usually with oral prednisone (50–150 mg/day) or high-dose IV methyl-Prednisolone (1 g/day) for 3-7 days. Thyroid hormone treatment is also included if required. This chapter explores Hashimoto's encephalopathy.

scholarly journals Outcome in patients with differentiated thyroid cancer with negative diagnostic whole-body scanning and detectable stimulated thyroglobulin

2003 ◽  
pp. 589-596 ◽  
Author(s):  
KM van Tol ◽  
PL Jager ◽  
EG de Vries ◽  
DA Piers ◽  
HM Boezen ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Tumor Location ◽  
Differentiated Thyroid Carcinoma ◽  
Post Treatment ◽  
Whole Body ◽  
High Dose ◽  
Serum Thyroglobulin ◽  
Thyroid Hormone Withdrawal ◽  
Iodine Treatment

BACKGROUND: Management of patients with differentiated thyroid carcinoma with negative diagnostic radioiodide scanning and increased serum thyroglobulin (Tg) concentrations is a widely debated problem. High-dose iodine-131 treatment of patients who have a negative (131)I diagnostic whole-body scan (WBS) is advocated. However, the therapeutic benefit of this "blind" treatment is not clear. OBJECTIVE: To investigate the course of serum Tg during thyroid hormone suppression therapy (Tg-on) and clinical outcome in patients with negative diagnostic (131)I scanning and increased serum Tg concentrations during thyroid hormone withdrawal (Tg-off), after treatment with high-dose (131)I. DESIGN: Retrospective single-center study. METHODS: Fifty-six patients were treated with a blind therapeutic dose of 150 mCi (131)I. Median follow-up from this treatment until the end of observation was 4.2 Years (range 0.5-13.5 Years). RESULTS: The post-treatment WBS revealed (131)I uptake in 28 patients, but none in the remaining 28 patients. In this study the Tg-on values did not change after treatment in either the positive or the negative post-treatment WBS group. During follow-up, 18 of the 28 patients with a positive post-treatment WBS achieved complete remission, compared with 10 of the 28 patients with a negative post-treatment WBS. Nine patients in the negative group died, but no patients died in the positive post-treatment group (P=0.001). CONCLUSIONS: High-dose iodine treatment in diagnostically negative patients who have a negative post-treatment scan seems to confer no additional value for tumor reduction and survival. In patients with a positive post-treatment scan, high-dose iodine treatment can be used as a diagnostic tool to identify tumor location, and a therapeutic effect may be present in individual cases.

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

2009 ◽  
Vol 44 (1) ◽  
pp. 1-11 ◽  
Author(s):  
Wendy M van der Deure ◽  
Robin P Peeters ◽  
Theo J Visser
Keyword(s):  
Genetic Variation ◽  
Thyroid Hormone ◽  
Organic Anion ◽  
Elevated Serum ◽  
Tissue Level ◽  
Psychomotor Retardation ◽  
Monocarboxylate Transporter ◽  
Organic Anion Transporting Polypeptides ◽  
The Central Nervous System ◽  
Molecular Aspects

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′,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.

scholarly journals Consequences of Monocarboxylate Transporter 8 Deficiency for Renal Transport and Metabolism of Thyroid Hormones in Mice

Endocrinology ◽  
2010 ◽  
Vol 151 (2) ◽  
pp. 802-809 ◽  
Author(s):  
Marija Trajkovic-Arsic ◽  
Theo J. Visser ◽  
Veerle M. Darras ◽  
Edith C. H. Friesema ◽  
Bernhard Schlott ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Thyroid Hormones ◽  
Psychomotor Retardation ◽  
High Serum ◽  
Monocarboxylate Transporter ◽  
Iodothyronine Deiodinase ◽  
Serum T4 ◽  
Mct8 Deficiency ◽  
Low Serum

Patients carrying inactivating mutations in the gene encoding the thyroid hormone transporting monocarboxylate transporter (MCT)-8 suffer from a severe form of psychomotor retardation and exhibit abnormal serum thyroid hormone levels. The thyroidal phenotype characterized by high-serum T3 and low-serum T4 levels is also found in mice mutants deficient in MCT8 although the cause of these abnormalities is still unknown. Here we describe the consequences of MCT8 deficiency for renal thyroid hormone transport, metabolism, and function by studying MCT8 null mice and wild-type littermates. Whereas serum and urinary parameters do not indicate a strongly altered renal function, a pronounced induction of iodothyronine deiodinase type 1 expression together with increased renal T3 and T4 content point to a general hyperthyroid state of the kidneys in the absence of MCT8. Surprisingly, accumulation of peripherally injected T4 and T3 into the kidneys was found to be enhanced in the absence of MCT8, indicating that MCT8 deficiency either directly interferes with the renal efflux of thyroid hormones or activates indirectly other renal thyroid hormone transporters that preferentially mediate the renal uptake of thyroid hormones. Our findings indicate that the enhanced uptake and accumulation of T4 in the kidneys of MCT8 null mice together with the increased renal conversion of T4 into T3 by increased renal deiodinase type 1 activities contributes to the generation of the low-serum T4 and the increase in circulating T3 levels, a hallmark of MCT8 deficiency.

Follow-up study on the effects of thyroid hormone administration on androgen metabolism of peripubertal rat Sertoli cells

1995 ◽  
Vol 132 (2) ◽  
pp. 236-241 ◽  
Author(s):  
ML Panno ◽  
M Salerno ◽  
M Lanzino ◽  
G De Luca ◽  
M Maggiolini ◽  
...  
Keyword(s):  
Thyroid Hormone ◽  
Sertoli Cells ◽  
Postnatal Life ◽  
Aromatase Activity ◽  
Testosterone Metabolism ◽  
Androgen Metabolism ◽  
Follow Up Study ◽  
Hormone Administration ◽  
Early Postnatal Life

Panno ML, Salerno M, Lanzino M, De Luca G, Maggiolini M, Straface SV, Prati M, Palmero S, Bolla E, Fugassa E, Andò S. Follow-up study on the effects of thyroid hormone administration on androgen metabolism of peripubertal rat sertoli cells. Eur J Endocrinol 1995;132:236–41. ISSN 0804–4643 The inhibitory effect of triiodothyronine (T3) given in early postnatal life on Sertoli cell proliferative activity, leading to their precocious terminal differentiation, has been demonstrated previously. However, data concerning the role of thyroid hormone on androgen metabolism of Sertoli cells during the same period are still lacking. In this study we performed a time-course investigation on the effects of T3 treatment on testosterone metabolism in Sertoli cells isolated from 2-, 3- and 4-weeks-old euthyroid rats. Triiodothyronine (3 μg/100 g body wt) was given ip., during the last week prior to sacrifice. Sertoli cells from all animal groups initially were cultured under basal conditions during the first 24 h and subsequently in the presence of testosterone (0.5 μmol/l) with or without T3 (1 nmol/l) for an additional 24 h. This treatment given to 2-week-old animals resulted in reduced testicular growth. As far as androgen metabolism is concerned, T3 in vivo and in vitro treatment in 2- and 3-week-old animals induced a lowering of dihydrotestosterone ± 3α-diol with an enhancement of the two other 5α-reduced androgens. The effect was much less pronounced in the oldest group. In both 2-and 3-week-old treated rats a marked reduction of oestradiol was observed, which indicates an inhibition of aromatase activity, mainly in younger animals. This enzyme has been reported to be extremely active in Sertoli cells of rats (of the same strain) between the age of 5 and 20 days, but it decreases rapidly thereafter. The results suggest that T3 given in early postnatal life could modify directly the androgen metabolism in Sertoli cells. Sebastiano Andò, Cattedra di Fisiopatologia Endocrina, Dipartimento di Biologia Cellulare, Università della Calabria, 87030 Arcavacata di Rende, Cosenza, Italy

Sign in / Sign up

Export Citation Format

Share Document