Functional analysis of monocarboxylate transporter 8 mutations identified in patients with X-linked psychomotor retardation and elevated serum triiodothyronine

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.

Friesema, Edith C H (författare)
Kester, Monique H A (författare)
Milici, Carmelina (författare)
Reeser, Maarten (författare)
Grüters, Annette (författare)
Barrett, Timothy G (författare)
Mancilla, Edna E (författare)
Svensson, Johan (författare)
Wemeau, Jean-Louis (författare)
da Silva Canalli, Maria Heloisa Busi (författare)
Lundgren, JohanLund University,Lunds universitet,Pediatrik, Lund,Sektion V,Institutionen för kliniska vetenskaper, Lund,Medicinska fakulteten,Paediatrics (Lund),Section V,Department of Clinical Sciences, Lund,Faculty of Medicine(Swepub:lu)pedi-jlu (författare)
McEntagart, Meriel E (författare)
Hopper, Neil (författare)
Arts, Willem Frans (författare)
Visser, Theo J (författare)
Pediatrik, LundSektion V (creator_code:org_t)

Ingår i:Journal of Clinical Endocrinology and Metabolism: The Endocrine Society92:6, s. 2378-23811945-71970021-972X

Av författaren/redakt...: Jansen, Jurgen; Friesema, Edith ...; Kester, Monique ...; Milici, Carmelin ...; Reeser, Maarten; Grüters, Annette; visa fler...; Barrett, Timothy ...; Mancilla, Edna E; Svensson, Johan; Wemeau, Jean-Lou ...; da Silva Canalli ...; Lundgren, Johan; McEntagart, Meri ...; Hopper, Neil; Arts, Willem Fra ...; Visser, Theo J; visa färre...

Om ämnet

MEDICIN OCH HÄLSOVETENSKAP: MEDICIN OCH HÄLS ...; och Klinisk medicin; och Pediatrik

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