posted on 2012-10-24, 08:55authored byE. Bochukova, N. Schoenmakers, M. Agostini, E. Schoenmakers, O. Rajanayagam, J. M. Keogh, E. Henning, J. Reinemund, D. Halsall, I. S. Farooqi, M. Gurnell, K. Chatterjee, K. Downes, A. Offiah, John W. R. Schwabe, E. Gevers, M. Dattani, M. Sarri, F. V. Khadem, K. Lindley, A. Albanese, M. Bain, F. Muntoni
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 wholeexome
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.
History
Citation
New England Journal of Medicine, 2012, 366 (3), pp. 243-249