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A Novel Thyroid Hormone Receptor-ß Mutation That Fails to Bind Nuclear Receptor Corepressor in a Patient as an Apparent Cause of Severe, Predominantly Pituitary Resistance to Thyroid Hormone

Departments of Medicine (S.Y.W., R.N.C., H.G., J.N., S.R., R.E.W.) and Pediatrics (S.R.), University of Chicago, Chicago Illinois 60645; and Department of Pediatrics (E.S., D.A.S., N.E.Y.), Abant Izzet Baysal University, Duzce Medical School, 14450 Duzce, Turkey

Address all correspondence and requests for reprints to: Roy E. Weiss, M.D., Ph.D., Thyroid Study Unit, Department of Medicine, University of Chicago, 5841 South Maryland Avenue, Mail Code 3090, Chicago, Illinois 60645. E-mail: rweiss{at}medicine.bsd.uchicago.edu.

Context: Resistance to thyroid hormone (RTH) is a dominantly inherited syndrome of variable tissue hyporesponsiveness to thyroid hormone (TH).

Objective: We report a newborn who presented with severe RTH (Mkar) with serum TSH 1500 mU/liter and free T₃ greater than 50 pM (normal 3.1–9.4) and free T₄ 25.3 pM (normal 12–22). We hypothesized that the RTH was due to reduced ligand binding and/or abnormal interaction with nuclear cofactors.

Design: These were prospective in vivo and in vitro studies.

Setting: The study was conducted at a tertiary care university hospital.

Patients: Patients included a newborn child and two other subjects with RTH.

Intervention: The effect of various TH-lowering agents in the subject with RTH was studied. In vitro studies including EMSA and mammalian two-hybrid assay as well as in vitro transfection studies were conducted.

Main Outcome Measures: Sequencing of the TH receptor (TR)ß and in vitro measurements of receptor-cofactor interaction were measured.

Results: Sequencing of the TRß demonstrated a de novo heterozygous mutation, 1590_1591insT, resulting in a frameshift producing a mutant TRß (mutTR)-ß with a 28-amino acid (aa) nonsense sequence and 2-amino acid carboxyl-terminal extension. The Mkar mutation was evaluated in comparison to three other TRß frameshift mutations in the carboxyl terminus. EMSA demonstrated that the Mkar mutTRß1 had impaired ability to recruit nuclear receptor corepressor but intact association with silencing mediator of retinoid and thyroid receptor (SMRT).

Conclusion: Our data suggest that alterations in codons 436–453 in helix 11 result in significantly diminished association with nuclear receptor corepressor but not SMRT. This novel mutTRß demonstrates nuclear corepressor specificity that results in severe predominantly pituitary RTH due to impaired release of SMRT.

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