title: Extended clinical phenotype, endocrine investigations and functional studies of a loss-of-function mutation A150V in the thyroid hormone specific transporter MCT8.
abstract: OBJECTIVE
  Thyroid hormones, besides having other functions, are known to be essential for the development of the human brain. Recently the monocarboxylate transporter 8 (MCT8) was identified as a thyroid hormone transporter which is expressed in different regions of the human brain. Here we describe in detail the clinical and biochemical features in response to thyroid hormone administration of a boy carrying an MCT8 mutation (A150V) in the second transmembrane domain.
  
  
  METHODS
  To study the functional impact of the mutation we performed triiodothyronine (T3) uptake, immunofluorescence and dimerization studies.
  
  
  RESULTS
  Thyroid hormone (l-thyroxine (LT4) and LT3) administration did not result in any significant clinical changes; however, with high doses of LT4, alone or in combination with T3, TSH suppression was achieved. We could show a robust uptake of (125)I-T3 for wild type (WT) MCT8, whereas no specific uptake could be detected for the mutant A150V. Subcellular localization of WT and mutant MCT8 revealed a strong cell surface expression for the WT MCT8, in contrast to A150V, which is mostly retained intracellularly with only weak cell surface expression. We could also demonstrate for the first time that WT MCT8 as well as the mutant are able to form multimers.
  
  
  CONCLUSIONS
  Our findings open a wide field of possible interaction within the central nervous system and will help to understand the crucial role of MCT8 in early fetal brain development.
authors.affiliation: Department of Pediatric Endocrinology, Charité Children's Hospital, Humboldt University Berlin, Augustenburger Platz 1, 13353 Berlin, Germany.
authors.forename: Heike
authors.initials: H
authors.lastname: Biebermann
authors.forename: Petra
authors.initials: P
authors.lastname: Ambrugger
authors.forename: Patrick
authors.initials: P
authors.lastname: Tarnow
authors.forename: Arpad
authors.initials: A
authors.lastname: von Moers
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schweizer
authors.forename: Annette
authors.initials: A
authors.lastname: Grueters
mesh_terms: D000818:Animals; D016466:CHO Cells; D002675:Child, Preschool; D006224:Cricetinae; D005260:Female; D006801:Humans; D008297:Male; D038901:X-Linked Intellectual Disability / Q000235:genetics* / Q000378:metabolism; D027501:Monocarboxylic Acid Transporters / Q000235:genetics* / Q000378:metabolism; D009123:Muscle Hypotonia / Q000235:genetics* / Q000378:metabolism; D017354:Point Mutation; D027981:Symporters; D013972:Thyrotropin / Q000097:blood; D013973:Thyrotropin-Releasing Hormone / Q000097:blood / Q000627:therapeutic use; D013974:Thyroxine / Q000097:blood / Q000627:therapeutic use; D014284:Triiodothyronine / Q000097:blood / Q000627:therapeutic use
chemical_list: D027501:Monocarboxylic Acid Transporters; C090735:SLC16A2 protein, human; D027981:Symporters; D014284:Triiodothyronine; D013973:Thyrotropin-Releasing Hormone; D013972:Thyrotropin; D013974:Thyroxine