title: Novel pathogenic mechanism suggested by ex vivo analysis of MCT8 (SLC16A2) mutations.
abstract: Monocarboxylate transporter 8 (MCT8; approved symbol SLC16A2) facilitates cellular uptake and efflux of 3,3',5-triiodothyronine (T3). Mutations in MCT8 are associated with severe psychomotor retardation, high serum T3 and low 3,3',5'-triiodothyronine (rT3) levels. Here we report three novel MCT8 mutations. Two subjects with the F501del mutation have mild psychomotor retardation with slightly elevated T3 and normal rT3 levels. T3 uptake was mildly affected in F501del fibroblasts and strongly decreased in fibroblasts from other MCT8 patients, while T3 efflux was always strongly reduced. Moreover, type 3 deiodinase activity was highly elevated in F501del fibroblasts, whereas it was reduced in fibroblasts from other MCT8 patients, probably reflecting parallel variation in cellular T3 content. Additionally, T3-responsive genes were markedly upregulated by T3 treatment in F501del fibroblasts but not in fibroblasts with other MCT8 mutations. In conclusion, mutations in MCT8 result in a decreased T3 uptake in skin fibroblasts. The much milder clinical phenotype of patients with the F501del mutation may be correlated with the relatively small decrease in T3 uptake combined with an even greater decrease in T3 efflux. If fibroblasts are representative of central neurons, abnormal brain development associated with MCT8 mutations may be the consequence of either decreased or increased intracellular T3 concentrations.
authors.affiliation: Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: W Edward
authors.initials: WE
authors.lastname: Visser
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: Edna
authors.initials: E
authors.lastname: Mancilla
authors.forename: Johan
authors.initials: J
authors.lastname: Lundgren
authors.forename: Marjo S
authors.initials: MS
authors.lastname: van der Knaap
authors.forename: Roelineke J
authors.initials: RJ
authors.lastname: Lunsing
authors.forename: Oebele F
authors.initials: OF
authors.lastname: Brouwer
authors.forename: Theo J
authors.initials: TJ
authors.lastname: Visser
mesh_terms: D001483:Base Sequence; D002478:Cells, Cultured; D005347:Fibroblasts; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics / Q000473:pathology; D008969:Molecular Sequence Data; D027501:Monocarboxylic Acid Transporters / Q000235:genetics*; D009154:Mutation; D012333:RNA, Messenger / Q000378:metabolism; D027981:Symporters; D013963:Thyroid Hormones / Q000378:metabolism; D014162:Transfection; D014284:Triiodothyronine / Q000378:metabolism
chemical_list: D027501:Monocarboxylic Acid Transporters; D012333:RNA, Messenger; C090735:SLC16A2 protein, human; D027981:Symporters; D013963:Thyroid Hormones; D014284:Triiodothyronine