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A Novel Mutation (E333D) in the Thyroid Hormone β Receptor Causing Resistance to Thyroid Hormone Syndrome
- Source :
- Experimental and Clinical Endocrinology & Diabetes. 114:569-576
- Publication Year :
- 2006
- Publisher :
- Georg Thieme Verlag KG, 2006.
-
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 beta receptor (TRbeta). Here, we report a novel natural RTH mutation (E333D) located in the large carboxy-terminal ligand binding domain of TRbeta. 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 TRbeta 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 TRbeta 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 TRbeta 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 TSHalpha promoter. Moreover, a dominant inhibition of the wild-type TRbeta counterpart transactivation function was observed on both a positive (F2-TRE) and a negative (TSHalpha) promoter. These results strongly suggest that the E333D TRbeta mutation is responsible for the RTH phenotype in the proposita's family.
- Subjects :
- Adult
Male
Thyroid Hormone Resistance Syndrome
Thyroid Hormones
medicine.medical_specialty
Endocrinology, Diabetes and Metabolism
Mutant
Electrophoretic Mobility Shift Assay
Biology
Thyroid hormone receptor beta
Endocrinology
Thyroid-stimulating hormone
Internal medicine
Internal Medicine
medicine
Humans
Receptor
Thyroid hormone receptor
Triiodothyronine
Thyroid
Gene Amplification
Thyroid Hormone Receptors beta
DNA
General Medicine
Pedigree
medicine.anatomical_structure
Amino Acid Substitution
Mutation
Female
hormones, hormone substitutes, and hormone antagonists
Hormone
Subjects
Details
- ISSN :
- 14393646 and 09477349
- Volume :
- 114
- Database :
- OpenAIRE
- Journal :
- Experimental and Clinical Endocrinology & Diabetes
- Accession number :
- edsair.doi.dedup.....c1fc53c471026d5a812adf3aa78789e9