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 &amp Metabolism (Impact Factor: 6.31). 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.
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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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