A mutation in the thyroid hormone receptor alpha gene

N Engl J Med. 2012 Jan 19;366(3):243-9. doi: 10.1056/NEJMoa1110296. Epub 2011 Dec 14.


Thyroid hormones exert their effects through alpha (TRα1) and beta (TRβ1 and TRβ2) receptors. Here we describe a child with classic features of hypothyroidism (growth retardation, developmental retardation, skeletal dysplasia, and severe constipation) but only borderline-abnormal thyroid hormone levels. Using whole-exome sequencing, we identified a de novo heterozygous nonsense mutation in a gene encoding thyroid hormone receptor alpha (THRA) and generating a mutant protein that inhibits wild-type receptor action in a dominant negative manner. Our observations are consistent with defective human TRα-mediated thyroid hormone resistance and substantiate the concept of hormone action through distinct receptor subtypes in different target tissues.

Publication types

  • Case Reports
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Child
  • Codon, Nonsense*
  • Female
  • Growth Disorders / drug therapy
  • Growth Disorders / genetics*
  • Heterozygote
  • Humans
  • Hypothyroidism / drug therapy
  • Hypothyroidism / genetics*
  • Models, Molecular
  • Protein Conformation
  • Thyroid Hormone Receptors alpha / chemistry
  • Thyroid Hormone Receptors alpha / genetics*
  • Thyroid Hormones / blood
  • Thyroxine / blood*
  • Thyroxine / therapeutic use*
  • Triiodothyronine / blood*


  • Codon, Nonsense
  • Thyroid Hormone Receptors alpha
  • Thyroid Hormones
  • Triiodothyronine
  • Thyroxine