title: Functional analysis of monocarboxylate transporter 8 mutations identified in patients with X-linked psychomotor retardation and elevated serum triiodothyronine.
abstract: BACKGROUND
  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).
  
  
  METHODS
  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.
  
  
  CONCLUSIONS
  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.affiliation: Department of Internal Medicine, Erasmus Medical Center, Room Ee502, Dr Molewaterplein 50, Rotterdam, The Netherlands.
authors.forename: Jurgen
authors.initials: J
authors.lastname: Jansen
authors.forename: Edith C H
authors.initials: EC
authors.lastname: Friesema
authors.forename: Monique H A
authors.initials: MH
authors.lastname: Kester
authors.forename: Carmelina
authors.initials: C
authors.lastname: Milici
authors.forename: Maarten
authors.initials: M
authors.lastname: Reeser
authors.forename: Annette
authors.initials: A
authors.lastname: Grüters
authors.forename: Timothy G
authors.initials: TG
authors.lastname: Barrett
authors.forename: Edna E
authors.initials: EE
authors.lastname: Mancilla
authors.forename: Johan
authors.initials: J
authors.lastname: Svensson
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Wemeau
authors.forename: Maria Heloisa
authors.initials: MH
authors.lastname: Busi da Silva Canalli
authors.forename: Johan
authors.initials: J
authors.lastname: Lundgren
authors.forename: Meriel E
authors.initials: ME
authors.lastname: McEntagart
authors.forename: Neil
authors.initials: N
authors.lastname: Hopper
authors.forename: Willem Frans
authors.initials: WF
authors.lastname: Arts
authors.forename: Theo J
authors.initials: TJ
authors.lastname: Visser
mesh_terms: D045744:Cell Line, Tumor; D018389:Codon, Nonsense; D017353:Gene Deletion; D040181:Genetic Diseases, X-Linked / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000378:metabolism; D027501:Monocarboxylic Acid Transporters / Q000235:genetics*; D009474:Neurons / Q000378:metabolism; D017354:Point Mutation; D011596:Psychomotor Disorders / Q000235:genetics* / Q000378:metabolism; D022821:RNA Splice Sites; D027981:Symporters; D014162:Transfection; D014284:Triiodothyronine / Q000097:blood* / Q000493:pharmacokinetics
chemical_list: D018389:Codon, Nonsense; D027501:Monocarboxylic Acid Transporters; D022821:RNA Splice Sites; C090735:SLC16A2 protein, human; D027981:Symporters; D014284:Triiodothyronine