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
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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.
    Full-text · Article · Aug 2011 · Thyroid Research
    • "Predicted complete inactivation Frints et al. (2008) 630insG N210fsX30 Predicted complete inactivation de Menezes-Filho et al. (2009) 631–644del R211fsX25 Predicted complete inactivation Jansen et al. (2007) 661G > A G221R Complete inactivation Schwartz et al. (2005), Vaurs-Barriere et al. (2009), Friesema et al. (2009) 670G > A A224T Not tested Raymond et al. (2008) 671C > T A224V Complete inactivation Friesema et al. (2004), Jansen et al. (2008) 689–691delTCT delF230 Complete inactivation Jansen et al. (2007), Schwartz et al. (2005) 703G > A V235M Complete inactivation Jansen et al. (2008), Schwartz et al. (2005) 706insGTG insV236 Complete to partial inactivation Kakinuma et al. (2005), Friesema et al. (2009), Kinne et al. (2009a) 733C > T R245X Complete inactivation Friesema et al. (2004), Jansen et al. (2008) 798–1G > C del267-370 Complete inactivation Jansen et al. (2007) 812G > A R271H Partial inactivation Jansen et al. (2007), Raymond et al. (2008), Kinne et al. (2009a) 844G > T G282C Partial inactivation Wood et al. (2008), Friesema et al. (2009) 962C > T P321L Complete inactivation Vaurs-Barriere et al. (2009) 1003C > T Q335X Predicted complete inactivation Herzovich et al. (2007), Vaurs-Barriere et al. (2009) 1018delC L340X Predicted complete inactivation Raymond et al. (2008) 1201G > A G401R Not tested Namba et al. (2009) 1212delT A405fsX12 Predicted complete inactivation Dumitrescu et al. (2004) 1301T > G L434W Complete to partial inactivation Schwartz et al. (2005), Jansen et al. (2008), Kinne et al. (2009a) 1333C > T R445C Not tested Vaurs-Barriere et al. (2009) 1343C > A S448X Complete inactivation Jansen et al. (2008), Schwartz et al. (2005) 1343–1344insGCCC S448fsX5 Predicted complete inactivation Mariotti et al. (2009) 1358A > T D453V Complete inactivation Friesema et al. (2009) 1412T > C L471P Complete inactivation Friesema et al. (2004) Jansen et al. (2008) 1500–1502delCTT delF501 Partial inactivation Visser et al. (2009) 1535T > C L512P Complete inactivation Dumitrescu et al. (2004) 1558C > T Q520X Predicted complete inactivation Vaurs-Barriere et al. (2009) 1560insCACA Q520fsX73 Predicted complete inactivation Unpublished 1610C > T P537L Complete inactivation Papadimitriou et al. (2008), Friesema et al. (2009) 1649delA Y550fsX17 Predicted complete inactivation Namba et al. (2009) 1673G > A G558D Partial inactivation Frints et al. (2008), Friesema et al. (2009) 1690G > A G564R Complete inactivation Visser et al. (2009) 1703T > C L568P Partial inactivation Jansen et al. (2008), Schwartz et al. (2005) 1826delC P609fsX70 Not tested Vaurs-Barriere et al. (2009) 1835delC P612fsX68 Partial inactivation Maranduba et al. (2006) N/A: not available. "
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    ABSTRACT: Thyroid hormone (TH) is crucial for the development of different organs, in particular the brain, as disturbances in TH supply cause severe neurological abnormalities. TH transporters are necessary for the intracellular availability of TH to have access to the deiodinases and nuclear receptors inside the cell. The clinical importance of TH transporters is dramatically shown in patients with mutations in MCT8, suffering from severe X-linked psychomotor retardation in combination with disturbed TH levels, especially high serum T(3) levels, now referred as Allan-Herndon-Dudley Syndrome (AHDS). Worldwide >45 families have now been identified with MCT8 mutations. Most MCT8 mutations result in a complete loss of TH transport function when tested in vitro, but some mutations show significant residual activity and are associated with a somewhat milder clinical phenotype. It is difficult to identify MCT8 patients only on the basis of the clinical characteristics of X-linked mental retardation. Therefore, the criterion for MCT8 mutation screening in these patients is the profile of increased T(3) and low-normal to low FT(4) serum levels.
    No preview · Article · Jun 2010 · Molecular and Cellular Endocrinology
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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.
    Full-text · Article · Jul 2008 · Molecular and Cellular Endocrinology
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