Decreased cellular T3 uptake and metabolism in Allan-Herndon-Dudley syndrome (AHDS) due to a novel mutation in the MCT8 thyroid hormone transporter

Journal of Medical Genetics (Impact Factor: 6.34). 06/2006; 43(5):457-60. DOI: 10.1136/jmg.2005.035840
Source: PubMed


We report a novel 1 bp deletion (c.1834delC) in the MCT8 gene in a large Brazilian family with Allan-Herndon-Dudley syndrome (AHDS), an X linked condition characterised by severe mental retardation and neurological dysfunction. The c.1834delC segregates with the disease in this family and it was not present in 100 control chromosomes, further confirming its pathogenicity. This mutation causes a frameshift and the inclusion of 64 additional amino acids in the C-terminal region of the protein. Pathogenic mutations in the MCT8 gene, which encodes a thyroid hormone transporter, results in elevated serum triiodothyronine (T3) levels, which were confirmed in four affected males of this family, while normal levels were found among obligate carriers. Through in vitro functional assays, we showed that this mutation decreases cellular T3 uptake and intracellular T3 metabolism. Therefore, the severe neurological defects present in the patients are due not only to deficiency of intracellular T3, but also to altered metabolism of T3 in central neurones. In addition, the severe muscle hypoplasia observed in most AHDS patients may be a consequence of high serum T3 levels.

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Available from: Edith C H Friesema, Oct 06, 2015
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    • "These mutations cause the Allan-Herndon-Dudley syndrome (AHDS) [1], which is an X-linked mental retardation. The affected patients show normal TSH (Thyroid-stimulating hormone, thyrotropin) but elevated T3 (3,3',5-triiodo-L-thyronine) and decreased T4 (3,3',5,5`-tetraiodo-L-thyronine) serum levels [2-6]. "
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    ABSTRACT: Thyroid hormones (TH) are essential for the development of the human brain, growth and cellular metabolism. Investigation of TH transporters became one of the emerging fields in thyroid research after the discovery of inactivating mutations in the Monocarboxylate transporter 8 (MCT8), which was found to be highly specific for TH transport. However, additional transmembrane transporters are also very important for TH uptake and efflux in different cell types. They transport TH as secondary substrates and include the aromatic amino acid transporting MCT10, the organic anion transporting polypeptides (e.g. OATP1C1, OATP1A2, OPTP1A4) and the large neutral amino acid transporters (LAT1 and LAT2). These TH transporters characteristically possess 12 transmembrane spanners but due to the strong differing sequences between the three transporter families we assume an identical conformation is not very likely. In contrast to the others, the LAT family members form a heterodimer with the escort protein 4F2hc/CD98. A comparison of sequence proportions, locations and types of functional sensitive features for TH transport discovered by mutations, revealed that transport sensitive charged residues occur as conserved amino acids only within each family of the transporter types but not in all putative TH transporters. Based on the lack of highly conserved sensitive charged residues throughout the three transporter families as a common counterpart for the amino acid moiety of the substrates, we conclude that the molecular transport mechanism is likely organized either a) by different molecular determinants in the divergent transporter types or b) the counterparts for the substrates` amino acid moiety at the transporter are not any charged side chains but other proton acceptors or donators. However, positions of transport sensitive residues coincide at transmembrane helix 8 in the TH transporter MCT8, OATP1C1 and another amino acid transporter, the L-cystine and L-glutamate exchanger xCT, which is highly homologous to LAT1 and LAT2. Here we review the data available and compare similarities and differences between these primary and secondary TH transporters regarding sequences, topology, potential structures, trafficking to the plasma membrane, molecular features and locations of transport sensitive functionalities. Thereby, we focus on TH transporters occurring in the blood-brain barrier.
    Thyroid Research 08/2011; 4 Suppl 1(Suppl 1):S7. DOI:10.1186/1756-6614-4-S1-S7
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    • "Uptake may be mediated by various types of transporters including those of the L type amino acid, organic anion and monocarboxylate families (Abe et al., 2002, Friesema et al., 2005, Taylor and Ritchie, 2007). Mutations recently identified in the MCT8 monocarboxylate transporter in human X-linked mental retardation and Allen-Herndon-Dudley syndrome suggest the importance of TH transport in neurological function (Dumitrescu et al., 2004, Friesema et al., 2004, Brockmann et al., 2005, Schwartz et al., 2005, Maranduba et al., 2006). Affected males exhibit psychomotor and speech defects. "
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    ABSTRACT: Thyroid hormone (TH) has a remarkable range of actions in the development and function of the nervous system. A multigenic picture is emerging of the mechanisms that specify these diverse functions in target tissues. Distinct responses are mediated by alpha and beta isoforms of TH receptor which act as ligand-regulated transcription factors. Receptor activity can be regulated at several levels including that of uptake of TH ligand and the activation or inactivation of ligand by deiodinase enzymes in target tissues. Processes under the control of TH range from learning and anxiety-like behaviour to sensory function. At the cellular level, TH controls events as diverse as axonal outgrowth, hippocampal synaptic activity and the patterning of opsin photopigments necessary for colour vision. Overall, TH coordinates this variety of events in both central and sensory systems to promote the function of the nervous system as a complete entity.
    Molecular and Cellular Endocrinology 07/2008; 287(1-2):1-12. DOI:10.1016/j.mce.2008.03.006 · 4.41 Impact Factor
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    • "Mutations in the MCT8 gene have been described in the X-linked psychomotor retardation syndrome (Allan–Herndon–Dudley syndrome). The patients exhibit increased serum T3 and severe neurological defects (Dumitrescu et al. 2004, Friesema et al. 2004, Maranduba et al. 2005, Schwartz et al. 2005). Mutations in this gene have also been found in the X-linked paroxysmal dyskinesia (Brockmann et al. 2005). "
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    ABSTRACT: Astrocyte cells clearly play a role in neural development, but nowadays their total action is seen as a far wider one. Recent findings consider them as stem cells, involved in the control of most facets of functional neural networks. Astrocytes play a central role in thyroid hormone metabolism in the brain, being the principal transporters of thyroxine from the blood, responsible for its conversion to 3,5,3'-triiodothyronine and hence supplying the neural tissues with the biologically active form of the hormone. Specific thyroid hormone transporters play an essential role in this regulatory system. The presence of thyroid hormone receptors has been demonstrated in cultured astrocytes. Furthermore, thyroid hormone regulates several aspects of astrocyte differentiation and maturation, including the production of extracellular matrix proteins and growth factors, and thus controls neuronal growth and neuritogenesis. Therefore, astrocytes are currently suggested as important mediators of thyroid hormone in neuronal development.
    Journal of Endocrinology 06/2006; 189(2):189-97. DOI:10.1677/joe.1.06680 · 3.72 Impact Factor
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