A Mutation in the Thyroid Hormone Receptor Alpha Gene

作者:Bochukova Elena; Schoenmakers Nadia; Agostini Maura; Schoenmakers Erik; Rajanayagam Odelia; Keogh Julia M; Henning Elana; Reinemund Jana; Gevers Evelien; Sarri Margarita; Downes Kate; Offiah Amaka; Albanese Assunta; Halsall David; Schwabe John W R; Bain Murray; Lindley Keith; Muntoni Francesco; Khadem Faraneh Vargha; Dattani Mehul; Farooqi I Sadaf; Gurnell Mark; Chatterjee Krishna*
来源:New England Journal of Medicine, 2012, 366(3): 243-249.
DOI:10.1056/NEJMoa1110296

摘要

Thyroid hormones exert their effects through alpha (TR alpha 1) and beta (TR beta 1 and TR beta 2) 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 TR alpha-mediated thyroid hormone resistance and substantiate the concept of hormone action through distinct receptor subtypes in different target tissues.