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

Departments of Internal Medicine (J.J., E.C.H.F., M.H.A.K., C.M., T.J.V.), and Child Neurology (W.F.A.), Erasmus Medical Center, 3015 GE DR Rotterdam, The Netherlands; Department of Pediatrics (M.R.), Juliana Children’s Hospital, 2566 MJ The Hague, The Netherlands; Department of Pediatric Endocrinology (A.G.), Charité Children’s Hospital, Humboldt University Berlin, 10099 Berlin, Germany; Department of Endocrinology (T.G.B.), Birmingham Children’s Hospital, Birmingham B4 6NH, United Kingdom; Institute of Biomedical Sciences (E.E.M.), Program of Pathophysiology, University of Chile, 6511224 Santiago, Chile; Department of Pediatrics (J.S.), Malmö University Hospital, S-205 02 Malmö, Sweden; Clinique Endocrinologique Marc Linquette (J.-L.W.), Centre Hospitalier Regional Universitaire de Lille, 59037 Lille, France; Medical Clinic Division (M.H.B.d.S.C.), Endocrinology Service, University Hospital, Federal University of Santa Catarina, 88040–970 Florianópolis, Brazil; Department of Child Neurology (J.L.), Children’s Hospital, University Hospital Lund, S-221 85 Lund, Sweden; and Departments of Clinical Genetics (M.E.M.), and Paediatric Endocrinology (N.H.), St. George’s Hospital, London SW17 0QT, United Kingdom

Address all correspondence and requests for reprints to: Theo J. Visser, Department of Internal Medicine, Erasmus Medical Center, Room Ee502, Dr Molewaterplein 50, 3015 GE Rotterdam, The Netherlands. E-mail: t.j.visser{at}erasmus.nl.

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: 1) T₃ uptake, 2) T₃ metabolism in cells cotransfected with human type 3 deiodinase, 3) immunoblotting, and 4) immunocytochemistry.

Results: 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.

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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