CONTEXT: 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. OBJECTIVE: The objective of this study was to determine the functional consequences of MCT8 mutations regarding transport of T(3). DESIGN: 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. 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 T(3) levels in these patients are caused by inactivation of the MCT8 transporter, preventing action and metabolism of T(3) in central neurons.
CONTEXT: 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. OBJECTIVE: The objective of this study was to determine the functional consequences of MCT8 mutations regarding transport of T(3). DESIGN: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. 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 MCT8Arg271His, which showed approximately 20% activity vs. wild-type MCT8. CONCLUSION: 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.
Authors: Simone Kersseboom; Sigrun Horn; W Edward Visser; Jiesi Chen; Edith C H Friesema; Catherine Vaurs-Barrière; Robin P Peeters; Heike Heuer; Theo J Visser Journal: Mol Endocrinol Date: 2014-12
Authors: Edith C H Friesema; Jurgen Jansen; Jan-Willem Jachtenberg; W Edward Visser; Monique H A Kester; Theo J Visser Journal: Mol Endocrinol Date: 2008-03-12
Authors: Artemis D Gika; Ata Siddiqui; Anthony J Hulse; Selvakumari Edward; Penny Fallon; Meriel E McEntagart; Wajanat Jan; Dragana Josifova; Tally Lerman-Sagie; James Drummond; Edward Thompson; Samuel Refetoff; Carsten G Bönnemann; Heinz Jungbluth Journal: Dev Med Child Neurol Date: 2009-10-07 Impact factor: 5.449
Authors: Simone Kersseboom; Gert-Jan Kremers; Edith C H Friesema; W Edward Visser; Wim Klootwijk; Robin P Peeters; Theo J Visser Journal: Mol Endocrinol Date: 2013-04-02
Authors: Alfonso Massimiliano Ferrara; Xiao-Hui Liao; Pilar Gil-Ibáñez; Teresa Marcinkowski; Juan Bernal; Roy E Weiss; Alexandra M Dumitrescu; Samuel Refetoff Journal: Endocrinology Date: 2013-05-21 Impact factor: 4.736
Authors: W Edward Visser; Nancy J Philp; Thamar B van Dijk; Wim Klootwijk; Edith C H Friesema; Jurgen Jansen; Philip W Beesley; Alexandra G Ianculescu; Theo J Visser Journal: Endocrinology Date: 2009-09-24 Impact factor: 4.736