A Novel Resistance to Thyroid Hormone Associated with a New Mutation (T329N) in the Thyroid Hormone Receptor β Gene

Resistance to thyroid hormone (RTH) is a syndrome of elevated serum thyroxine, inappropriately "normal" serum thyrotropin (TSH) and reduced thyroid hormone responsiveness associated with point mutations in the thyroid hormone receptor-β (TRβ) gene. We describe a novel point mutation resulting in a cytosine for adenine substitution at nucleotide 1271 (exon 9) that results in the substitution of threonine for asparagine (T329N). This mutation was identified in a 30-year-old woman who was investigated for recurrent spontaneous abortions and was found to have RTH. Dextrothyroxine (D-T4) therapy was instituted. At 8 mg per day 2 pregnancies followed with the delivery of a healthy boy and an RTH-affected girl another miscarriage occurred on D-T4 treatment at 6 mg per day. The T329N mutation, which was also identified in the daughter, markedly reduces the affinity of TRβ for triiodothyronine (T 3 ). Formation of T329N mutant TR homodimers and heterodimers with RXRα on thyroid hormone response element F2 (TRE F2) was not affected, but the ability of T 3 to interrupt T329N mutant TRβ homodimerization was markedly reduced. The T329N mutant TRβ was transcriptionally inactive in transient expression assays. In cotransfection assays with wild-type TRβ 1 , the mutant TRβ 1 functioned in a dominant negative manner. The results suggest that the T329N mutation in the T 3 -binding domain of TRβ is responsible for RTH in the proposita's family.