Exp Clin Endocrinol Diabetes 2006; 114(10): 569-576
DOI: 10.1055/s-2006-956169
Article

© J. A. Barth Verlag in Georg Thieme Verlag KG · Stuttgart · New York

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

M. Maraninchi 1 , N. Bourcigaux 2 , A. Dace 3 , C. El-Yazidi 1 , C. Malezet-Desmoulins 1 , M. Krempf 2 , J. Torresani 1 , A. Margotat 1
  • 1UMR 476 INSERM/1260 INRA, Université de la Méditerranée, Faculté de Médecine, Marseille, France
  • 2Clinique d'Endocrinologie Maladies Métaboliques et nutrition, Nantes, France
  • 3CARB, Rockville MD USA
Further Information

Publication History

Received: March 4, 2006 First decision: May 8, 2006

Accepted: May 24, 2006

Publication Date:
19 December 2006 (online)

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.

References

Correspondence

Dr. Alain Margotat

UMR 476 INSERM/1260 INRA

Faculté de Médecine

27 boulevard Jean Moulin

13385 Marseille

Cedex 5

France

Phone: +33/049/132 43 81

Fax: +33/049/178 21 01

Email: alain.margotat@medecine.univ-mrs.fr