A Novel Syndrome Combining Thyroid and Neurological Abnormalities Is Associated with Mutations in a Monocarboxylate Transporter Gene

Department of Human Genetics, University of Chicago, Chicago, IL 60637, USA.
The American Journal of Human Genetics (Impact Factor: 10.93). 02/2004; 74(1):168-75. DOI: 10.1086/380999
Source: PubMed


Thyroid hormones are iodothyronines that control growth and development, as well as brain function and metabolism. Although thyroid hormone deficiency can be caused by defects of hormone synthesis and action, it has not been linked to a defect in cellular hormone transport. In fact, the physiological role of the several classes of membrane transporters remains unknown. We now report, for the first time, mutations in the monocarboxylate transporter 8 (MCT8) gene, located on the X chromosome, that encodes a 613-amino acid protein with 12 predicted transmembrane domains. The propositi of two unrelated families are males with abnormal relative concentrations of three circulating iodothyronines, as well as neurological abnormalities, including global developmental delay, central hypotonia, spastic quadriplegia, dystonic movements, rotary nystagmus, and impaired gaze and hearing. Heterozygous females had a milder thyroid phenotype and no neurological defects. These findings establish the physiological importance of MCT8 as a thyroid hormone transporter.

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Available from: Alexandra Dumitrescu, Mar 23, 2014
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    • "Since TH metabolizing deiodinases as well as TH receptors are intracellularly active, TH transporter deficiency can greatly compromise tissue TH homeostasis. As the most prominent example, inactivating mutations in the monocarboxylate transporter 8 (MCT8; SCL16A2) gene, which encodes a very specific TH transporter (5), result in an abnormal serum TH profile with highly elevated levels of the receptor active hormone T3 (3,3′,5,-triiodothyronine) and low T4 concentrations of the prohormone T4 (3,3′,5,5′-tetraiodothyronine) (6–8). Moreover, patients with MCT8 mutations suffer from a severe form of psychomotor retardation suggesting that in the absence of MCT8, neural differentiation and function is severely impaired possibly due to insufficient TH supply during critical stages of development (9). "
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    ABSTRACT: For a comprehensive description of the tissue-specific thyroidal state under normal as well as under pathophysiological conditions it is of utmost importance to include thyroid hormone (TH) transporters in the analysis as well. The current knowledge of the cell-specific repertoire of TH transporters, however, is still rather limited, although several TH transporting proteins have been identified. Here, we describe the temporal and spatial distribution pattern of the most prominent TH transporters in the postnatal mouse brain. For that purpose, we performed radioactive in situ hybridization studies in order to analyze the cellular mRNA expression pattern of the monocarboxylate transporters Mct8 and Mct10, the L-type amino acid transporters Lat1 and Lat2 as well as the organic anion transporting peptide Oatp1c1 at different postnatal time points. Highest TH transporter expression levels in the CNS were observed at postnatal day 6 and 12, while hybridization signal intensities visibly declined after the second postnatal week. The only exception was Mct10 for which the strongest signals could be observed in white matter regions at postnatal day 21 indicating that this transporter is preferentially expressed in mature oligodendrocytes. Whereas Mct8 and Lat2 showed an overlapping neuronal mRNA expression pattern in the cerebral cortex, hippocampus, and in the hypothalamus, Oatp1c1 and Lat1 specific signals were most prominent in capillary endothelial cells throughout the CNS. In the choroid plexus, expression of three transporters (Mct8, Lat2, and Oatp1c1) could be detected, whereas in other brain areas (e.g., striatum, thalamus, and brain stem nuclei) only one of the transporter candidates appeared to be present. Overall, our study revealed a distinct mRNA distribution pattern for each of the TH transporter candidates. Further studies will reveal to which extent these transporters contribute to the cell-specific TH uptake and efflux in the mouse CNS.
    Full-text · Article · Jun 2014 · Frontiers in Endocrinology
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    • "urogenesis , migration and differenti - ation of cells to synaptogenesis and myelination ( Bernal , 2007 ) . This critical influence of T3 on the maturing brain is harshly illustrated by the severe neurological dysfunction in individuals with genetic muta - tions of the monocarboxylate 8 transporter that is essential for cellular transport of T3 ( Dumitrescu et al . , 2004 ; Friesema et al . , 2004 ) . It is becoming increasingly apparent that many of these processes persist at a low level in the adult hypothalamus , raising the question of whether seasonal cycles of growth , body weight and reproduction are a recapit - ulation of these early developmental mechanisms ( Hazlerigg and Lincoln , 2011 ) ."
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    ABSTRACT: This article is part of a Special Issue “Energy Balance”. Seasonal cycles of adiposity and body weight reflecting changes in both food intake and energy expenditure are the norm in mammals that have evolved in temperate and polar habitats. Innate circannual rhythmicity and direct responses to the annual change in photoperiod combine to ensure that behavior and energy metabolism are regulated in anticipation of altered energetic demands such as the energetically costly processes of hibernation, migration, and lactation. In the last decade, major progress has been made into identifying the central mechanisms that underlie these profound long-term changes in behavior and physiology. Surprisingly they are distinct from the peptidergic and aminergic systems in the hypothalamus that have been identified in studies of the laboratory mouse and rat and implicated in timing meal intervals and in short-term responses to caloric restriction. Comparative studies across rodents, ungulates and birds reveal that tanycytes embedded in the ependymal layer of the third ventricle play a critical role in seasonal changes because they regulate the local availability of thyroid hormone. Understanding how this altered hormonal environment might regulate neurogenesis and plasticity in the hypothalamus should provide new insight into development of strategies to manage appetite and body weight.
    Full-text · Article · Jun 2014 · Hormones and Behavior
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    • "The most specific and physiologically relevant transporters for THs identified so far are the monocarboxylate transporter 8 (MCT8, SLC16A2), and the organic anion transporting polypeptide 1C1 (OATP1C1, SLCO1C1). MCT8 mutations cause an X-linked syndrome with severe psychomotor retardation and elevated serum T3 levels, indicating the importance of this transporter in TH availability to the brain (11, 12). Other transporters may also contribute to this process although their specific roles are less clear. "
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    ABSTRACT: Thyroid hormone (TH) action is exerted mainly through regulation of gene expression by binding of T3 to the nuclear receptors. T4 plays an important role as a source of intracellular T3 in the central nervous system via the action of the type 2 deiodinase (D2), expressed in the astrocytes. A model of T3 availability to neural cells has been proposed and validated. The model contemplates that brain T3 has a double origin: a fraction is available directly from the circulation, and another is produced locally from T4 in the astrocytes by D2. The fetal brain depends almost entirely on the T3 generated locally. The contribution of systemic T3 increases subsequently during development to account for approximately 50% of total brain T3 in the late postnatal and adult stages. In this article, we review the experimental data in support of this model, and how the factors affecting T3 availability in the brain, such as deiodinases and transporters, play a decisive role in modulating local TH action during development.
    Full-text · Article · May 2014 · Frontiers in Endocrinology
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