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Functional analysis of MCT8 mutations identified in patients with X-linked psychomotor retardation and elevated serum triiodothyronine.

Jansen, Jurgen; Friesema, Edith C H; Kester, Monique H A; Milici, Carmelina; Reeser, Maarten; Grüters, Annette; Barrett, Timothy G; Mancilla, Edna E; Svensson, Johan and Wemeau, Jean-Louis, et al. (2007) In Journal of Clinical Endocrinology and Metabolism 92(6). p.2378-2381
Abstract
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... (More)
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. (Less)
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published
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Journal of Clinical Endocrinology and Metabolism
volume
92
issue
6
pages
2378 - 2381
publisher
The Endocrine Society
external identifiers
  • wos:000247061700063
  • scopus:34347216037
ISSN
1945-7197
DOI
10.1210/jc.2006-2570
language
English
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yes
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b09275c1-58dc-48d8-97d8-41cf783de1cd (old id 166632)
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http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17356046&dopt=Abstract
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2007-07-23 11:46:56
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2017-11-19 04:11:48
@article{b09275c1-58dc-48d8-97d8-41cf783de1cd,
  abstract     = {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.},
  author       = {Jansen, Jurgen and Friesema, Edith C H and Kester, Monique H A and Milici, Carmelina and Reeser, Maarten and Grüters, Annette and Barrett, Timothy G and Mancilla, Edna E and Svensson, Johan and Wemeau, Jean-Louis and da Silva Canalli, Maria Heloisa Busi and Lundgren, Johan and McEntagart, Meriel E and Hopper, Neil and Arts, Willem Frans and Visser, Theo J},
  issn         = {1945-7197},
  language     = {eng},
  number       = {6},
  pages        = {2378--2381},
  publisher    = {The Endocrine Society},
  series       = {Journal of Clinical Endocrinology and Metabolism},
  title        = {Functional analysis of MCT8 mutations identified in patients with X-linked psychomotor retardation and elevated serum triiodothyronine.},
  url          = {http://dx.doi.org/10.1210/jc.2006-2570},
  volume       = {92},
  year         = {2007},
}