A novel resistance to thyroid hormone associated with a new mutation (T329N) in the thyroid hormone receptor beta gene

Resistance to thyroid hormone (RTH) is a syndrome of elevated serum thyroxi ne, inappropriately "normal" serum thyrotropin (TSH) and reduced thyroid ho rmone responsiveness associated with point mutations in the thyroid hormone receptor-beta (TR beta) gene. We describe a novel point mutation resulting in a cytosine for adenine substitution at nucleotide 1271 (exon 9) that re sults in the substitution of threonine for asparagine (T329N). This mutatio n was identified in a 30-year-old woman who was investigated for recurrent spontaneous abortions and was found to have RTH. Dextrothyroxine (D-T4) the rapy was instituted. At 8 mg per day 2 pregnancies followed with the delive ry of a healthy boy and an RTH-affected girl another miscarriage occurred o n D-T4 treatment at 6 mg per day. The T329N mutation, which was also identi fied in the daughter, markedly reduces the affinity of TR beta for triiodot hyronine (T-3) Formation of T329N mutant TR homodimers and heterodimers wit h RXR alpha on thyroid hormone response element F2 (TRE F2) was not affecte d, but the ability of T-3 to interrupt T329N mutant TR beta homodimerizatio n was markedly reduced. The T329N mutant TR beta was transcriptionally inac tive in transient expression assays. In cotransfection assays with wild-typ e TR beta(1), the mutant TR beta(1) functioned in a dominant negative manne r. The results suggest that the T329N mutation in the T-3-binding domain of TR beta is responsible for RTH in the proposita's family.