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

Objective: We report a newborn who presented with severe RTH (Mkar) with serum TSH 1500 mU/L and FT₃>50 pM (normal 3.1-9.4) and FT₄ 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: Prospective in vivo and in vitro studies.

Setting: A tertiary care University Hospital.

Patients: A newborn child and 2 other subjects with RTH.

Intervention: Effect of various TH lowering agents in the subject with RTH. In vitro studies including Electrophoretic mobility shift assay (EMSA) and mammalian two-hybrid assay as well as in vitro transfection studies.

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

Results: Sequencing of the TR demonstrated a de novo heterozygous mutation, 1590 1591insT, resulting in a frameshift producing a mutTR with a 28 amino acid (aa) nonsense sequence and 2 aa carboxyl-terminal extension. The Mkar mutation was evaluated in comparison to 3 other TR frameshift mutations in the carboxyl-terminus. EMSA demonstrated that the Mkar mutTR1 had impaired ability to recruit NCoR 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 NCoR, but not SMRT. This novel mutTR demonstrates nuclear corepressor specificity that results in severe predominantly pituitary RTH due to impaired release of SMRT.