This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Behr, M. Articles by Loos, U. Search for Related Content PubMed PubMed Citation Articles by Behr, M. Articles by Loos, U.

Deoxyribonucleic Acid Binding and Transcriptional Silencing by a Truncated c-erbAß1 Thyroid Hormone Receptor Identified in a Severely Retarded Patient with Resistance to Thyroid Hormone¹

Department Internal Medicine I (M.B., U.L.), University of Ulm, D-89070 Ulm, Germany; and Department of Medicine (D.B.R.), University of Birmingham, Queen Elizabeth Hospital, B15 2TH Edgbaston, Birmingham, United Kingdom

Address all correspondence and requests for reprints to: Prof. Dr. med. Ulrich Loos, Abteilung Innere Medizin I, Medizinische Klinik und Poliklinik, Universität Ulm, Robert-Koch-Str. 8, D-89070 Ulm, Germany.

We describe the analysis of a thyroid hormone receptor (TR) ß causing resistance to thyroid hormone, the patient exhibiting hypothyroid symptoms (severe mental retardation, hypoactivity, obesity) and hyperthyroid symptoms (tachycardia, low serum cholesterol) and, additionally, relative early puberty, advanced bone age, and short stature. The patient was heterozygous, with a point mutation producing a premature stop-codon in TRß-gene exon 10, resulting in a 28-amino acid carboxy-terminal deletion in the cognate TRß (TRß-EZ). T₃ binding was abolished. Homodimer binding of TRß-EZ to DR4- and F2-T₃ response elements (TREs) was weaker, and to a palindromic TRE (PAL) was stronger than that of wild-type TRß (TRß-WT) in the absence of T₃. T₃ dissociated TRß-WT, but not TRß-EZ homodimer, from DR4, F2, and Pal. Heterodimerization of TRß-EZ with retinoid x receptor ß was seen. TRß-EZ repressed basal thymidine kinase-promotor activity, coupled to DR4, F2, or PAL. Silencing of basal gene transcription via PAL was weaker, and via DR4 and F2 was more pronounced, compared with TRß-WT. TRß-EZ had a strong dominant negative effect on TRß-WT, attenuated in a TRE- and cell-specific manner by high T₃ concentrations. Finally, the degree of TRß-EZ homodimer-binding affinity to DNA did not correlate with the degree of transcriptional dominant negative activity.

This article has been cited by other articles:

				S. A. Phillips, P. Rotman-Pikielny, J. Lazar, S. Ando, P. Hauser, M. C. Skarulis, F. Brucker-Davis, and P. M. Yen Extreme Thyroid Hormone Resistance in a Patient with a Novel Truncated TR Mutant J. Clin. Endocrinol. Metab., November 1, 2001; 86(11): 5142 - 5147. [Abstract] [Full Text] [PDF]

				C. Asteria, O. Rajanayagam, T. N. Collingwood, L. Persani, R. Romoli, D. Mannavola, P. Zamperini, F. Buzi, F. Ciralli, V. K. K. Chatterjee, et al. Prenatal Diagnosis of Thyroid Hormone Resistance J. Clin. Endocrinol. Metab., February 1, 1999; 84(2): 405 - 410. [Abstract] [Full Text]