Two Novel Cases of Resistance to Thyroid Hormone Due to Mutation.

Resistance to thyroid hormone alpha (RTHα) is a rare and under-recognized genetic disease caused by mutations of , the gene encoding thyroid hormone receptor α1 (TRα1). We report here two novel missense mutations (M259T, T273A) in patients with RTHα. We combined biochemical and cellular assays with modeling to assess the capacity of mutant TRα1 to bind triiodothyronine (T3), to heterodimerize with RXR, to interact with transcriptional coregulators, and to transduce a T3 transcriptional response. M259T, and to a lower extent T273A, reduces the affinity of TRα1 for T3. Their negative influence is only reverted by large excess of T3. The severity of the two novel RTHα cases originates from a reduction in the binding affinity of TRα1 mutants to T3 and thus correlates with the incapacity of corepressors to dissociate from TRα1 mutants in the presence of T3.