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

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

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA

NATL ACAD SCIENCES

Lugar: Washington DC, USA; Año: 2013 p. 7850 - 7855

0027-8424

Genetic evidence from patients with mutations of the thyroid hormone receptor a gene (THRA) indicates that the dominant negative activity of mutants underlies the pathological manifestations. However, the molecular mechanisms by which TRa1 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 TRa1 mutants to properly release the nuclear corepressors (NCORs), thereby inhibiting thyroid hormone-mediated transcription activity. We crossed Thra1PV mice, expressing a dominant negative TRa1 mutant (TRa1PV), with mice expressing a mutant Ncor1 allele (Ncor1DID mice) that cannot recruit the TR or PV mutant. TRa1PV shares the same C-terminal mutated sequences as those of patients with frameshift mutations of the THRA gene. Remarkably, NCOR1DID ameliorated abnormaliities in the thyroid-pituitary axis of Thra1PV/+ mice. The severe retarded growth, infertility, and delayed bone development were partially reverted in Thra1PV/+ mice expressing NCOR1DID. The impaired adipogenesis was partially corrected by de-repression of peroxisome-proliferator activated receptor gamma and CCAAT/enhancer- binding protein a gene, due to the inability of TRa1PV to recruit NCOR1DID to form a repressor complex. Thus, the aberrant recruitment of NCOR1 by TRa1 mutants could lead to clinical hypothyroidism in humans. Therefore, therapies aimed at the TRa1-NCOR1 interaction or its downstream actions could be tested as potential targets in treating TRa1 mutant-mediated hypothyroidism in patients.