A novel 1297-1304delGCCTGCCA mutation in the exon 10 of the thyroid hormone receptor β gene causes resistance to thyroid hormone.

INTRODUCTION

Resistance to the thyroid hormone (RTH) is an inherited syndrome of reduced tissue responsiveness to hormonal action caused by mutations located in the ligand-binding domain and adjacent hinge region of the thyroid hormone receptor β (TRβ) gene.

PATIENT

The patient in this study, a 42-year-old Caucasian male, came to medical attention because he experienced atrial fibrillation. Clinical evaluation showed a small and diffuse goiter and biochemical tests revealed markedly elevated concentrations of total T(4), total T(3), and free T(4), normal thyroid-stimulating hormone (TSH) values and slightly increased I(131) thyroid uptake at 24 hours. The thyroperoxidase, thyroglobulin, and TSH receptor antibodies were positive. He was treated with cabergoline plus methimazole. This treatment was stopped because of the inconsistent response, monotherapy with tri-iodothyroacetic acid (TRIAC) was then prescribed after molecular diagnosis confirmed RTH syndrome.

METHODS

The exons 9 and 10 of the TRβ gene, including splicing signals and the flanking intronic regions of each intron, were amplified with PCR. DNA sequences from each amplified fragment were performed with the Taq polymerase-based chain terminator method and using the specific TRβ forward and reverse primers.

RESULTS

Direct sequence analysis of the exons 9 and 10 of the TRβ gene revealed an eight basepair deletion, 1297-1304delGCCTGCCA in exon 10. The mutation produces a frameshift at amino acid 433 and introduces a stop codon TGA at position 461, 85 nucleotides downstream from deletion. This alteration was not detected in either the father or mother of the patient, suggesting a de novo mutation that was confirmed by DNA fingerprint analysis.

CONCLUSIONS

In the present study we have identified a novel sporadic mutation corresponding to 1297-1304delGCCTGCCA deletion in the activating function 2 (AF-2) region of TRβ. To our knowledge, this is the first time that the presence of a partial deletion of eight nucleotides in the TRβ has been reported.