NUCLEAR RECEPTOR COREPRESSOR (NCOR1) REGULATES IN VIVO ACTIONS OF A MUTATED THYROID HORMONE RECEPTOR α.

FOZZATTI, LAURA; DONG-WOOK KIM; PARK JEONG WON; WILLINGHAM MARK C; HOLLENBERG ANTHONY N; CHENG SHEUE-YANN

NATL ACAD SCIENCES

Lugar: Washington DC, USA; Año: 2013 p. 7850 - 7850

enetic evidence from patients with mutations of the thyroid hor- mone receptor α gene (THRA) indicates that the dominant nega- tive activity of mutants underlies the pathological manifestations. However, the molecular mechanisms by which TRα1 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 TRα1 mutants to properly re- lease the nuclear corepressors (NCORs), thereby inhibiting thyroid hormone-mediated transcription activity. We crossed Thra1PV mice, expressing a dominant negative TRα1 mutant (TRα1PV), with mice expressing a mutant Ncor1 allele (Ncor1ΔID mice) that cannot recruit the TR or PV mutant. TRα1PV shares the same C-terminal mutated sequences as those of patients with frameshift mutations of the THRA gene. Remarkably, NCOR1ΔID ameliorated abnormal- ities in the thyroid-pituitary axis of Thra1PV/+ mice. The seve