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

A mutation in the thyroid hormone receptor alpha gene.

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  • 1University of Cambridge Metabolic Research Laboratories and National Institute for Health Research Cambridge Biomedical Research Centre, Institute of Metabolic Science, Addenbrooke's Hospital, Cambridge, United Kingdom.

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  • N Engl J Med. 2012 Oct 11;367(15):1474. Khadem, Faraneh Vargha [corrected to Vargha-Khadem, Faraneh].


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.

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