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Three Novel Mutations at Serine 314 in the Thyroid Hormone ß Receptor Differentially Impair Ligand Binding in the Syndrome of Resistance to Thyroid Hormone¹

Department of Medicine, University of Cambridge, Addenbrooke’s Hospital (M.G., O.R., M.A., R.J.D.C.-B., V.K.K.C.), Cambridge, United Kingdom CB2 2QQ; the Dipartimento di Endocrinologia e Metabolismo, Università di Pisa (M.A., E.M., A.P.), 56124 Pisa, Italy; the Department of Clinical Biochemistry, Leicester Royal Infirmary (T.W.), Leicester, United Kingdom LE1 5WW; the Department of Endocrinology, University Hospital (P.M.J.Z.), Utrecht, The Netherlands; the Department of Clinical Chemistry, Eemland Hospital (F.v.d.H.), 3800 BM Amersfoort, The Netherlands; and the Medical Research Council Laboratory of Molecular Biology (J.W.R.S.), Cambridge, United Kingdom CB2 2QH; Department of Endocrinology (Ar.d.W), Eemland Hospital, 3800 BM Amersfoort, The Netherlands

Address all correspondence and requests for reprints to: Dr. V. K. K. Chatterjee, Department of Medicine, University of Cambridge, Level 5, Addenbrooke’s Hospital, Hills Road, Cambridge, United Kingdom CB2 2QQ. E-mail:kkc1{at}mole.bio.cam.ac.uk

The syndrome of resistance to thyroid hormone is associated with diverse mutations in the ligand-binding domain of the thyroid hormone ß receptor, localizing to three clusters around the hormone binding cavity. Here, we report three novel resistance to thyroid hormone mutations (S314C, S314F, and S314Y), due to different nucleotide substitutions in the same codon, occurring in six separate families. Functional characterization of these mutant receptors showed marked differences in their properties. S314F and S314Y receptor mutants exhibited significant transcriptional impairment in keeping with negligible ligand binding and were potent dominant negative inhibitors of wild-type receptor action. In contrast, the S314C mutant bound ligand with reduced affinity, such that its functional impairment and dominant negative activity manifest at low concentrations of thyroid hormone, but are more reversible at higher T₃ concentrations. The degree of functional impairment of mutant receptors in vitro may correlate with the magnitude of thyroid dysfunction in vivo. Modelling these mutations using the crystal structure of thyroid hormone receptor ß shows why ligand binding is perturbed and why the phenylalanine/tyrosine mutations are more deleterious than cysteine.

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