Article

Functional Analysis of Monocarboxylate Transporter 8 Mutations Identified in Patients with X-Linked Psychomotor Retardation and Elevated Serum Triiodothyronine

Humboldt-Universität zu Berlin, Berlín, Berlin, Germany
Journal of Clinical Endocrinology & Metabolism (Impact Factor: 6.21). 07/2007; 92(6):2378-81. DOI: 10.1210/jc.2006-2570
Source: PubMed

ABSTRACT

T(3) action in neurons is essential for brain development. Recent evidence indicates that monocarboxylate transporter 8 (MCT8) is important for neuronal T(3) uptake. Hemizygous mutations have been identified in the X-linked MCT8 gene in boys with severe psychomotor retardation and elevated serum T(3) levels.
The objective of this study was to determine the functional consequences of MCT8 mutations regarding transport of T(3).
MCT8 function was studied in wild-type or mutant MCT8-transfected JEG3 cells by analyzing: 1) T(3) uptake, 2) T(3) metabolism in cells cotransfected with human type 3 deiodinase, 3) immunoblotting, and 4) immunocytochemistry.
The mutations identified in MCT8 comprise four deletions (24.5 kb, 2.4 kb, 14 bp, and 3 bp), three missense mutations (Ala224Val, Arg271His, and Leu471Pro), a nonsense mutation (Arg245stop), and a splice site mutation (94 amino acid deletion). All tested mutants were inactive in uptake and metabolism assays, except MCT8 Arg271His, which showed approximately 20% activity vs. wild-type MCT8.
These findings support the hypothesis that the severe psychomotor retardation and elevated serum T(3) levels in these patients are caused by inactivation of the MCT8 transporter, preventing action and metabolism of T(3) in central neurons.

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    • "JEG3 hu - man placental choriocarcinoma cells transfected with mutant hu - man SLC16A2 cDNA show an almost complete loss of T3 transport capacity for mutations associated with severe phenotypes , whereas significant residual transport is observed for mutations associated with milder phenotypes ( e . g . , patients who are able to walk or speak ) [ Jansen et al . , 2007 , 2008 ] . More recently , analyses using patient fibroblasts , considered a more physiological model , have also been undertaken to study MCT8 function . These have demon - strated a strong decrease ( ∼70% ) in T3 uptake in fibroblasts from three severely affected patients , whereas T3 uptake was decreased to a lesser extent ( 50% ) in"
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    ABSTRACT: SLC16A2, the gene for the 2(nd) member of the solute carrier family 16 (monocarboxylic acid transporter), located on chromosome Xq13.2, encodes a very efficient thyroid hormone (TH) transporter: monocarboxylate transporter 8, MCT8. Its loss of function is responsible in males for a continuum of psychomotor retardation ranging from severe (no motor acquisition, no speech) to mild (ability to walk with help and a few words of speech). Triiodothyronine uptake measurement in transfected cells and, more recently, patient fibroblasts, has been described to study the functional consequences of MCT8 mutations. Here we describe 3 novel MCT8 mutations, including one missense variation not clearly predicted to be damaging but found in a severely affected patient. Functional studies in fibroblasts and JEG3 cells demonstrate the usefulness of both cellular models in validating the deleterious effects of a new MCT8 mutation if there is still a doubt as to its pathogenicity. Moreover, the screening of fibroblasts from a large number of patient fibroblasts and of transfected mutations has allowed us to demonstrate that JEG3 transfected cells are more relevant than fibroblasts in revealing a genotype-phenotype correlation.
    Full-text · Article · Jul 2013 · Human Mutation
    • "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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    • "Another example of the difficulty in linking serum TH to adverse outcomes is provided by the recent observation in humans of an abnormal TH profile in boys with a genetic mutation in the T 3 -specific transporter monocarboxylate anion transporter 8 (MCT8). In all cases, serum T 3 is elevated, but serum T 4 , free T 4 , and TSH may be low, normal, or elevated (Jansen et al. 2007). Thus, the elevated serum T 3 appears to be a biomarker of the MCT8 mutation among the patients evaluated , although it is not the only mechanism by which T 3 can become elevated. "
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    ABSTRACT: BACKGROUND: There is increasing evidence in humans and in experimental animals for a relationship between exposure to specific environmental chemicals and perturbations in levels of critically important thyroid hormones (THs). Identification and proper interpretation of these relationships are required for accurate assessment of risk to public health. OBJECTIVES: We review the role of TH in nervous system development and specific outcomes in adults, the impact of xenobiotics on thyroid signaling, the relationship between adverse outcomes of thyroid disruption and upstream causal biomarkers, and the societal implications of perturbations in thyroid signaling by xenobiotic chemicals. DATA SOURCES: We drew on an extensive body of epidemiologic, toxicologic, and mechanistic studies. DATA SYNTHESIS: THs are critical for normal nervous system development, and decreased maternal TH levels are associated with adverse neuropsychological development in children. In adult humans, increased thyroid-stimulating hormone is associated with increased blood pressure and poorer blood lipid profiles, both risk factors for cardiovascular disease and death. These effects of thyroid suppression are observed even within the "normal" range for the population. Environmental chemicals may affect thyroid homeostasis by a number of mechanisms, and multiple chemicals have been identified that interfere with thyroid function by each of the identified mechanisms. CONCLUSIONS: Individuals are potentially vulnerable to adverse effects as a consequence of exposure to thyroid-disrupting chemicals. Any degree of thyroid disruption that affects TH levels on a population basis should be considered a biomarker of adverse outcomes, which may have important societal outcomes.
    Full-text · Article · Jul 2009 · Environmental Health Perspectives
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