Two novel cases of resistance to thyroid hormone due to THRA mutation (RTHalpha).

BACKGROUND: Resistance to thyroid hormone alpha (RTHalpha) is a rare and under-recognized genetic disease caused by mutations of THRA, the gene encoding thyroid hormone receptor alpha1 (TRalpha1). We report here the discovery of two novel patients with missense mutations (M259T, T273A) causing RTHalpha. METHODS: We combined biochemical and cellular assays with in silico modeling to assess the capacity of mutant TRalpha1 to bind T3, to heterodimerize with RXR, to interact with transcriptional coregulators and to transduce a T3 transcriptional response. RESULTS: M259T, and to a lower extent T273A, reduce the affinity of TRalpha1 for T3. Their negative influence is only reverted by large excess of T3. CONCLUSIONS: The severity of the two novel RTHalpha cases originates from a reduction in the binding affinity of TRalpha1 mutants to T3 and thus correlates with the incapacity of corepressors to dissociate from TRalpha1 mutants in the presence of T3.