Functional Characterization of a Novel Variant of the Thyroid Hormone Receptor Alpha in a Child with Developmental Delay and Abnormal Thyroid Function.

Abstract

Background: Resistance to thyroid hormone α (RTHα) is a rare disorder caused by pathogenic THRA variants. We investigated the molecular basis of RTHα in a child with developmental delay, dysmorphic features, and a suggestive biochemical profile.

Methods: Whole-exome sequencing identified a de novo THRA variant. Cell-based transcriptional assays assessed thyroid hormone responsiveness, coactivator dependence, and dominant-negative activity.

Results: A novel heterozygous frameshift variant, c.1125_1132dup (p.Gly378Alafs*2), truncating the ligand-binding domain, was identified. The mutant receptor showed markedly impaired responses to triiodothyronine (T3) and TRIAC. CBP/p300 and PGC1α failed to activate the variant, supporting loss of function. Co-expression studies demonstrated strong inhibition of wild-type THRA activity that was not rescued by high T3 concentrations, indicating a potent dominant-negative effect. Disruption of DNA binding abolished this interference, showing that DNA occupancy is required.

Conclusions: These findings expand the spectrum of pathogenic THRA variants and provide new insight into transcriptional repression in RTHα.