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Functional analysis of monocarboxylate transporter 8 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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organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Clinical Endocrinology and Metabolism
volume
92
issue
6
pages
2378 - 2381
publisher
Oxford University Press
external identifiers
  • wos:000247061700063
  • scopus:34347216037
ISSN
1945-7197
DOI
10.1210/jc.2006-2570
language
English
LU publication?
yes
id
b09275c1-58dc-48d8-97d8-41cf783de1cd (old id 166632)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17356046&dopt=Abstract
date added to LUP
2016-04-01 16:39:32
date last changed
2022-04-22 23:34:21
@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    = {{Oxford University Press}},
  series       = {{Journal of Clinical Endocrinology and Metabolism}},
  title        = {{Functional analysis of monocarboxylate transporter 8 mutations identified in patients with X-linked psychomotor retardation and elevated serum triiodothyronine}},
  url          = {{http://dx.doi.org/10.1210/jc.2006-2570}},
  doi          = {{10.1210/jc.2006-2570}},
  volume       = {{92}},
  year         = {{2007}},
}