Novel Thyroid Hormone Receptor β Gene Variant (F245L) Causing Mild Resistance to Thyroid Hormone

TL;DR

A new THRB gene variant (F245L) was found to cause mild resistance to thyroid hormone in a Japanese man, with functional and clinical evidence supporting its role.

Contribution

This is the first report providing functional evidence of the pathogenicity of the THRB F245L variant.

Findings

The F245L variant showed only mildly reduced transcriptional activity at physiological triiodothyronine concentrations.

The patient's Rathke cleft cyst decreased in size independently of thyroid function changes.

The F245L variant is located near other mild-phenotype-associated residues in the ligand-binding domain.

Abstract

A novel thyroid hormone receptor β (THRB) variant was identified in a 34-year-old Japanese man with resistance to thyroid hormone β (RTHβ). He presented with mildly elevated serum thyroid hormone and nonsuppressed TSH levels in the absence of a goiter. Genetic testing revealed a novel heterozygous missense variant of THRB (c.733T > C; p.F245L). In vitro transient gene expression assays demonstrated that the F245L mutant receptor had only mildly reduced transcriptional activity at physiological and low triiodothyronine concentrations and did not exhibit apparent dominant-negative activity. The F245L variant is located within a known cluster of functionally important residues in the ligand-binding domain, adjacent to R243Q, R243W, and P247L, which are also associated with mild phenotypes. Although the patient had a Rathke cleft cyst, its size decreased over time, whereas the thyroid function remained unchanged, suggesting an independent occurrence of the 2 conditions. To the best of our knowledge, this is the first report to provide functional evidence of the pathogenicity of the F245L variant. This case highlights the importance of integrating clinical, biochemical, and molecular data to diagnose and characterize RTHβ, particularly in patients with subtle phenotypes and novel genetic variants.

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