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

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.