title: Resistance to thyroid hormone mediated by defective thyroid hormone receptor alpha.
abstract: BACKGROUND
  Thyroid hormone acts via receptor subtypes (TRα1, TRβ1, TRβ2) with differing tissue distributions, encoded by distinct genes (THRA, THRB). THRB mutations cause a disorder with central (hypothalamic-pituitary) resistance to thyroid hormone action with markedly elevated thyroid hormone and normal TSH levels.
  
  
  METHODS
  This review describes the clinical features, genetic and molecular pathogenesis of a homologous human disorder mediated by defective THRA. Clinical features include growth retardation, skeletal dysplasia and constipation associated with low-normal T4 and high-normal T3 levels and a low T4/T3 ratio, together with subnormal reverse T3 levels. Heterozygous TRa1 mutations in affected individuals generate defective mutant receptors which inhibit wild-type receptor action in a dominant negative manner.
  
  
  CONCLUSIONS
  Mutations in human TRα1 mediate RTH with features of hypothyroidism in particular tissues (e.g. skeleton, gastrointestinal tract), but are not associated with a markedly dysregulated pituitary-thyroid axis.
  
  
  CONCLUSIONS
  Human THRA mutations could be more common but may have eluded discovery due to the absence of overt thyroid dysfunction. Nevertheless, in the appropriate clinical context, a thyroid biochemical signature (low T4/T3 ratio, subnormal reverse T3 levels), may enable future identification of cases. This article is part of a Special Issue entitled Thyroid hormone signalling.
authors.affiliation: Institute of Metabolic Science, University of Cambridge, UK.
authors.forename: Nadia
authors.initials: N
authors.lastname: Schoenmakers
authors.forename: Carla
authors.initials: C
authors.lastname: Moran
authors.forename: Robin P
authors.initials: RP
authors.lastname: Peeters
authors.forename: Theo
authors.initials: T
authors.lastname: Visser
authors.forename: Mark
authors.initials: M
authors.lastname: Gurnell
authors.forename: Krishna
authors.initials: K
authors.lastname: Chatterjee
mesh_terms: D006801:Humans; D009154:Mutation; D037021:Thyroid Hormone Receptors alpha / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D018382:Thyroid Hormone Resistance Syndrome / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D013963:Thyroid Hormones / Q000235:genetics / Q000378:metabolism / Q000502:physiology*
chemical_list: D037021:Thyroid Hormone Receptors alpha; D013963:Thyroid Hormones