Pathogenic mechanism of mutations in the thyroid hormone receptor β gene

Resistance to thyroid hormone (RTH) is characterized by a variable degree of reduced tissue sensitivity to thyroid hormone (TH). It is usually caused by mutations in the TH receptor-β (TRβ) gene.

To characterize clinical and molecular features of a Thai patient with RTH. Functional significance of the identified mutation as well as other uncharacterized TRβ mutations was also investigated.

Exons 3-10 of the TRβ gene were assessed by PCR-sequencing. Functional characterization of the mutant TRβ was determined by the luciferase reporter system.

A mutation in exon 9 of the TRβ gene resulting in a methionine to threonine substitution at codon 313 was identified. The functional consequence of this mutation and other uncharacterized known mutations (p.I276L, p.I280S, p.L330S, p.G344A, p.M442T) was evaluated by transfection studies. Four out of 6 had a significant impairment of T3-dependent transactivation. When co-transfected with the wild-type TRβ, all exhibited a dominant negative effect.

A de novo mutation was identified in the patient with clinical diagnosis of RTH. Our findings provide a strong support that interfering with the T3-mediated transcriptional activation of the wild-type TRβ independent of the ability to activate transcription is a major pathogenic mechanism causing RTH.