Endocrine Abstracts

Patients with mutations of the thyroid hormone receptor α (THRA) gene display classic features of hypothyroidism with growth and developmental retardation, skeletal dysplasia, and severe constipation, but with only borderline-abnormal thyroid hormone levels. These patients are heterozygotes, indicating that TRα1 mutants act in a dominant negative manner to mediate the clinical manifestations in these patients. However, the molecular mechanisms by which these TRα1 mutants act in vivo in a dominant negative fashion are not known. We tested the hypothesis that the severe hypothyroidism in patients with THRA mutations results from an inability of TRα1 mutants to properly release the nuclear corepressors (NCORs), thereby inhibiting thyroid hormone (T₃)-mediated transcription activity. We crossed Thra1^PV mice expressing a dominant negative TRα1 mutant (TRα1PV) with mice expressing a mutant Ncor1 allele (Ncor1^ΔID mice). TRα1PV has the same mutated C-terminal sequence (-TLPRGL) with truncated termination at amino acid L406 as did two patients with frameshift mutations of the THRA gene. The NCOR1ΔID protein globally expressed by the mutant Ncor1 allele cannot recruit the TR or PV mutant. Remarkably, the expression of NCOR1ΔID ameliorated abnormalities in the pituitary-thyroid axis of Thra1^PV/+ mice. The severe retarded growth, infertility, and delayed bone development were partially reverted in Thra1^PV/+ mice expressing NCOR1ΔID. The impaired adipogenesis was partially corrected by de-repression of peroxisome-proliferator activated receptor γ and CCAAT/enhancer-binding protein α genes, due to the inability of TRα1PV to recruit NCOR1ΔID. These in vivo data suggest that the aberrant recruitment of NCOR1 by TRα1 mutants could lead to clinical hypothyroidism in humans. Therefore, therapies aimed at the TRα1-NCOR1 interaction or its downstream actions could be tested as potential targets in treating TRα1 mutant-mediated hypothyroidism in patients.

Declaration of funding

The present research was supported by the Intramural Research Program at the Center for Cancer Research, National Cancer Institute, National Institutes of Health.