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Submitted on November 22, 2006
Accepted on March 7, 2007
Department of Internal Medicine, Erasmus MC, Rotterdam, The Netherlands; Department of Pediatrics, Juliana Children's Hospital, The Hague, The Netherlands; Department of Pediatric Endocrinology, Charité Children's Hospital, Humbolt University Berlin, Berlin, Germany; Department of Endocrinology, Birmingham Children's Hospital, Birmingham, UK; Institute of Biomedical Sciences, Program of Pathophysiology, University of Chile, Santiago, Chile; Department of Pediatrics, Malmö University Hospital, Malmö, Sweden; Clinique Endocrinologique Marc Linquette, Centre Hospitalier Regional Universitaire de Lille, Lille, France; Medical Clinic Division, Endocrinology Service, University Hospital, Federal University of Santa Catarina, Florianópolis, Brasil; Department of Child Neurology, Children's Hospital, University Hospital Lund, Sweden; Department of Clinical Genetics, St. George's Hospital, London, UK.; Department of Paediatric Endocrinology, St. George's Hospital, London, UK.; Department of Child Neurology, Erasmus MC- Sophia, Rotterdam, The Netherlands
Context: T3 action in neurons is essential for brain development. Recent evidence indicates that monocarboxylate transporter 8 (MCT8) is important for neuronal T3 uptake. Hemizygous mutations have been identified in the X-linked MCT8 gene in boys with severe psychomotor retardation and elevated serum T3 levels.
Objective: The objective of this study was to determine the functional consequences of MCT8 mutations regarding transport of T3.
Design: MCT8 function was studied in wild-type or mutant MCT8 transfected JEG3 cells by analyzing a) T3 uptake, b) T3 metabolism in cells cotransfected with human type 3 deiodinase, c) Immunoblotting, and d) immunocytochemistry.
Results: The mutations identified in MCT8 comprise 4 deletions (24.5 kb, 2.4 kb, 14 bp and 3 bp), 3 missense mutations (Ala224Val, Arg271His, 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 
20% activity vs. wild-type MCT8.
Conclusion: These findings support the hypothesis that the severe psychomotor retardation and elevated serum T3 levels in these patients are caused by inactivation of the MCT8 transporter, preventing action and metabolism of T3 in central neurons.
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