Mutation and functional analysis of the thyroid hormone receptor β gene in thai families with resistance to thyroid hormone

Abstract

Resistance to thyroid hormones (RTH) is an autosomal dominant inherited syndrome characterized by a variable degree of reduced tissue sensitivity to thyroid hormone (TH) resulting in elevated serum TH levels, inappropriately normal or elevated serum thyroid stimulating hormone (TSH) levels, and a goiter. It is caused by mutations in the thyroid hormone receptor (TR) β gene. Most mutations resulted in either a decreased T3 binding activity or impaired interaction with one of the cofactors involved in the mediation of TH action. In addition, the mutant TRβ molecules interfere with the function of the normal TRβ, a phenomenon called dominant negative effect (DNE). We described a de novo mutation in a Thai patient with RTH who had a heterozygous missense mutation in exon 9 of the TRβ gene, resulting in a methionine to threonine substitution at codon 313 (p.M313T). This mutation has been previously reported in other populations but never been investigated for its functional significance. We further explored functional properties of this de novo mutant TRβ and compared with other uncharacterized known mutations (I276L, I280S, L330S, G344A, M442T) by using the luciferase reporter gene assay. All except the I276L and G344A had a significant impairment of T3-dependent transactivation activity. In addition, all exhibited a dominant negative effect in the presence of 10-7 M of T3. These findings provide a strong support that interfering with the T3-mediated transcriptional activation of the wild-type TRβ is a major mechanism causing RTH.