A Novel Mutation (E333D) in the Thyroid Hormone β Receptor Causing Resistance to Thyroid Hormone Syndrome

Abstract

Resistance to thyroid hormone (RTH) is an inherited syndrome characterized by elevated serum thyroid hormones (TH), failure to suppress pituitary thyroid stimulating hormone (TSH) secretion, and variable peripheral tissue responsiveness to TH. The disorder is associated with diverse mutations in the thyroid hormone β receptor (TRβ). Here, we report a novel natural RTH mutation (E333D) located in the large carboxy-terminal ligand binding domain of TRβ. The mutation was identified in a 22-year-old French woman coming to medical attention because of an increasing overweight. Biochemical tests showed elevated free thyroxine (T4: 20.8 pg/ml (normal, 8.5-18)) and triiodothyronine (T3: 5.7 pg/ml (normal, 1.4-4)) in the serum, together with an inappropriately nonsuppressed TSH level of 4.7 mU/ml (normal, 0.4-4). Her father and her brother's serum tests also showed biochemical abnormalities consistent with RTH. Direct sequencing of the TRβ gene revealed a heterozygous transition 1284A>C in exon 9 resulting in substitution of glutamic acid 333 by aspartic acid residue (E333D). Further functional analyses of the novel TRβ mutant were conducted. We found that the E333D mutation neither significantly affected the affinity of the receptor for T3 nor modified heterodimer formation with retinoid X receptor (RXR) when bound to DNA. However, in transient transfection assays, the E333D TRβ mutant exhibited impaired transcriptional regulation on two distinct positively regulated thyroid response elements (F2- and DR4-TREs) as well as on the negatively regulated human TSHα promoter. Moreover, a dominant inhibition of the wild-type TRβ counterpart transactivation function was observed on both a positive (F2-TRE) and a negative (TSHα) promoter. These results strongly suggest that the E333D TRβ mutation is responsible for the RTH phenotype in the proposita's family.

Key words

Thyroid hormone receptor - mutation - hormone resistance

References

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