A Mutation in the Thyroid Hormone Receptor Alpha Gene.Bochukova E, Schoenmakers N, Agostini M, Schoenmakers E, Rajanayagam O, Keogh JM, Henning E, Reinemund J, Gevers E, Sarri M, Downes K, Offiah A, Albanese A, Halsall D, Schwabe JW, Bain M, Lindley K, Muntoni F, Khadem FV, Dattani M, Farooqi IS, Gurnell M, Chatterjee K. N Engl J Med. 2011 Dec 14. [Epub ahead of print]

AbstractThyroid 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. Comment– This is a report of the first person identified with a mutation in the TRα gene, that appeared to cause clear hypothyroidism, but was not readily reversed by T4 treatment. T4 was 3.3 ug/dl, T3 155 ng/dl, TSH 1.04 mU/l, normal TBG, IGF-1 low at 59 ng/ml, BP82/51, and BMR 3.49M/day (nl=4.06). Sequencing identified one heterozygous mutation (c1207 G>T in TRα), present in multiple tissues but not in 200 control alleles, that could explain the phenotype. The abnormal receptor did not bind T3, did not activate a control gene, mediated suppression of basal promoter activity, and was a “dominate negative”. Treatment with T4 suppressed TSH, but failed to normalize growth or sluggish bowel function. The biochemical findings have many similarities to those seen in mice with dominant negative TRα mutations, but interestingly TRα null mice do not have abnormalities similar to the patient. A combination of hypothyroid features, near normal T4 with slightly elevated T3, and low rT3 may characterize the syndrome. Effective treatment is unclear at present