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.
SCOPE OF REVIEW: 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.
MAJOR 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.
GENERAL SIGNIFICANCE: 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.