title: A novel thyroid hormone receptor-beta mutation that fails to bind nuclear receptor corepressor in a patient as an apparent cause of severe, predominantly pituitary resistance to thyroid hormone.
abstract: BACKGROUND
  Resistance to thyroid hormone (RTH) is a dominantly inherited syndrome of variable tissue hyporesponsiveness to thyroid hormone (TH).
  
  
  OBJECTIVE
  We report a newborn who presented with severe RTH (Mkar) with serum TSH 1500 mU/liter and free T(3) greater than 50 pm (normal 3.1-9.4) and free T(4) 25.3 pm (normal 12-22). We hypothesized that the RTH was due to reduced ligand binding and/or abnormal interaction with nuclear cofactors.
  
  
  METHODS
  These were prospective in vivo and in vitro studies.
  
  
  METHODS
  The study was conducted at a tertiary care university hospital.
  
  
  METHODS
  Patients included a newborn child and two other subjects with RTH.
  
  
  METHODS
  The effect of various TH-lowering agents in the subject with RTH was studied. In vitro studies including EMSA and mammalian two-hybrid assay as well as in vitro transfection studies were conducted.
  
  
  METHODS
  Sequencing of the TH receptor (TR)beta and in vitro measurements of receptor-cofactor interaction were measured.
  
  
  RESULTS
  Sequencing of the TRbeta demonstrated a de novo heterozygous mutation, 1590_1591insT, resulting in a frameshift producing a mutant TRbeta (mutTR)-beta with a 28-amino acid (aa) nonsense sequence and 2-amino acid carboxyl-terminal extension. The Mkar mutation was evaluated in comparison to three other TRbeta frameshift mutations in the carboxyl terminus. EMSA demonstrated that the Mkar mutTRbeta1 had impaired ability to recruit nuclear receptor corepressor but intact association with silencing mediator of retinoid and thyroid receptor (SMRT).
  
  
  CONCLUSIONS
  Our data suggest that alterations in codons 436-453 in helix 11 result in significantly diminished association with nuclear receptor corepressor but not SMRT. This novel mutTRbeta demonstrates nuclear corepressor specificity that results in severe predominantly pituitary RTH due to impaired release of SMRT.
authors.affiliation: Department of Medicine, University of Chicago, 5841 South Maryland Avenue, Mail Code 3090, Chicago, Illinois 60645, USA.
authors.forename: Sharon Y
authors.initials: SY
authors.lastname: Wu
authors.forename: Ronald N
authors.initials: RN
authors.lastname: Cohen
authors.forename: Enver
authors.initials: E
authors.lastname: Simsek
authors.forename: Dursun A
authors.initials: DA
authors.lastname: Senses
authors.forename: Nese E
authors.initials: NE
authors.lastname: Yar
authors.forename: Helmut
authors.initials: H
authors.lastname: Grasberger
authors.forename: Janet
authors.initials: J
authors.lastname: Noel
authors.forename: Samuel
authors.initials: S
authors.lastname: Refetoff
authors.forename: Roy E
authors.initials: RE
authors.lastname: Weiss
mesh_terms: D000595:Amino Acid Sequence; D002648:Child; D004268:DNA-Binding Proteins / Q000235:genetics; D024202:Electrophoretic Mobility Shift Assay; D005347:Fibroblasts / Q000378:metabolism; D016368:Frameshift Mutation / Q000235:genetics* / Q000502:physiology*; D017930:Genes, Reporter / Q000235:genetics; D051548:Histone Acetyltransferases; D006801:Humans; D007231:Infant, Newborn; D008297:Male; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism*; D056971:Nuclear Receptor Co-Repressor 1; D056985:Nuclear Receptor Co-Repressor 2; D056920:Nuclear Receptor Coactivator 1; D010902:Pituitary Gland / Q000503:physiopathology*; D010957:Plasmids / Q000235:genetics; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D037042:Thyroid Hormone Receptors beta / Q000235:genetics*; D018382:Thyroid Hormone Resistance Syndrome / Q000235:genetics* / Q000503:physiopathology*; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection
chemical_list: D004268:DNA-Binding Proteins; C539127:NCOR1 protein, human; C539130:NCOR2 protein, human; D009687:Nuclear Proteins; D056971:Nuclear Receptor Co-Repressor 1; D056985:Nuclear Receptor Co-Repressor 2; D012097:Repressor Proteins; D037042:Thyroid Hormone Receptors beta; D014157:Transcription Factors; D051548:Histone Acetyltransferases; C538859:NCOA1 protein, human; D056920:Nuclear Receptor Coactivator 1