Nuclear receptor corepressor (NCOR1) regulates in vivo actions of a mutated thyroid hormone receptor α

Genetic evidence from patients with mutations of the thyroid hormone receptor alpha gene (THRA) indicates that the dominant negative activity of mutants underlies the pathological manifestations. However, the molecular mechanisms by which TR alpha 1 mutants exert dominant negative activity in vivo are not clear. We tested the hypothesis that the severe hypothyroidism in patients with THRA mutations is due to an inability of TR alpha 1 mutants to properly release the nuclear corepressors (NCORs), thereby inhibiting thyroid hormone-mediated transcription activity. We crossed Thra1(PV) mice, expressing a dominant negative TR alpha 1 mutant (TR alpha 1PV), with mice expressing a mutant Ncor1 allele (Ncor1(Delta ID) mice) that cannot recruit the TR or PV mutant. TR alpha 1PV shares the same C-terminal mutated sequences as those of patients with frameshift mutations of the THRA gene. Remarkably, NCOR1 Delta ID ameliorated abnormalities in the thyroid-pituitary axis of Thra1(PV/+) mice. The severe retarded growth, infertility, and delayed bone development were partially reverted in Thra1(PV/+) mice expressing NCOR1 Delta ID. The impaired adipogenesis was partially corrected by de-repression of peroxisome-proliferator activated receptor gamma and CCAAT/enhancerbinding protein a gene, due to the inability of TR alpha 1PV to recruit NCOR1 Delta ID to form a repressor complex. Thus, the aberrant recruitment of NCOR1 by TR alpha 1 mutants could lead to clinical hypothyroidism in humans. Therefore, therapies aimed at the TR alpha 1-NCOR1 interaction or its downstream actions could be tested as potential targets in treating TR alpha 1 mutant-mediated hypothyroidismin patients.