title: Further Insights into the Allan-Herndon-Dudley Syndrome: Clinical and Functional Characterization of a Novel MCT8 Mutation.
abstract: BACKGROUND
  Mutations in the thyroid hormone (TH) transporter MCT8 have been identified as the cause for Allan-Herndon-Dudley Syndrome (AHDS), characterized by severe psychomotor retardation and altered TH serum levels. Here we report a novel MCT8 mutation identified in 4 generations of one family, and its functional characterization.
  
  
  METHODS
  Proband and family members were screened for 60 genes involved in X-linked cognitive impairment and the MCT8 mutation was confirmed. Functional consequences of MCT8 mutations were studied by analysis of [125I]TH transport in fibroblasts and transiently transfected JEG3 and COS1 cells, and by subcellular localization of the transporter.
  
  
  RESULTS
  The proband and a male cousin demonstrated clinical findings characteristic of AHDS. Serum analysis showed high T3, low rT3, and normal T4 and TSH levels in the proband. A MCT8 mutation (c.869C>T; p.S290F) was identified in the proband, his cousin, and several female carriers. Functional analysis of the S290F mutant showed decreased TH transport, metabolism and protein expression in the three cell types, whereas the S290A mutation had no effect. Interestingly, both uptake and efflux of T3 and T4 was impaired in fibroblasts of the proband, compared to his healthy brother. However, no effect of the S290F mutation was observed on TH efflux from COS1 and JEG3 cells. Immunocytochemistry showed plasma membrane localization of wild-type MCT8 and the S290A and S290F mutants in JEG3 cells.
  
  
  CONCLUSIONS
  We describe a novel MCT8 mutation (S290F) in 4 generations of a family with Allan-Herndon-Dudley Syndrome. Functional analysis demonstrates loss-of-function of the MCT8 transporter. Furthermore, our results indicate that the function of the S290F mutant is dependent on cell context. Comparison of the S290F and S290A mutants indicates that it is not the loss of Ser but its substitution with Phe, which leads to S290F dysfunction.
authors.affiliation: Regional Genetics Program, Children's Hospital of Eastern Ontario, and Children's Hospital of Eastern Ontario Research Institute, University of Ottawa, Ottawa, Canada.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Armour
authors.affiliation: Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Simone
authors.initials: S
authors.lastname: Kersseboom
authors.affiliation: Department of Paediatrics, Divisions of Neurology and Clinical and Metabolic Genetics, Hospital for Sick Children, Toronto, Canada.
authors.forename: Grace
authors.initials: G
authors.lastname: Yoon
authors.affiliation: Department of Internal Medicine, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: Theo J
authors.initials: TJ
authors.lastname: Visser
mesh_terms: D000293:Adolescent; D000328:Adult; D002478:Cells, Cultured; D005260:Female; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism*; D006579:Heterozygote; D006801:Humans; D007124:Immunoenzyme Techniques; D008297:Male; D038901:X-Linked Intellectual Disability / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008875:Middle Aged; D027501:Monocarboxylic Acid Transporters / Q000235:genetics*; D009123:Muscle Hypotonia / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009133:Muscular Atrophy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D027981:Symporters; D014284:Triiodothyronine / Q000378:metabolism*
chemical_list: D027501:Monocarboxylic Acid Transporters; D012333:RNA, Messenger; C090735:SLC16A2 protein, human; D027981:Symporters; D014284:Triiodothyronine