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

Resistance to thyroid hormone alpha (RTH alpha) is a rare and under-recognized genetic disease caused by mutations of THRA, the gene encoding thyroid hormone receptor alpha 1 (TR alpha 1). We report here two novel THRA missense mutations (M259T, T273A) in patients with RTH alpha. We combined biochemical and cellular assays with in silico modeling to assess the capacity of mutant TR alpha 1 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 TR alpha 1 for T3. Their negative influence is only reverted by large excess of T3. The severity of the two novel RTH alpha cases originates from a reduction in the binding affinity of TR alpha 1 mutants to T3 and thus correlates with the incapacity of corepressors to dissociate from TR alpha 1 mutants in the presence of T3.