A NEW POINT MUTATION (C446R) IN THE THYROID-HORMONE RECEPTOR-BETA GENE OF A FAMILY WITH RESISTANCE TO THYROID-HORMONE

Resistance to thyroid hormone (RTH) is a condition of impaired end-org an responsiveness to thyroid hormone characterized by goiter and eleva ted thyroid hormone levels with an inappropriately normal TSH. RTH has been associated with mutations in the thyroid hormone receptor-beta ( TR beta) gene. We report studies carried out in 21 members of a family (F119), 12 of whom exhibited the RTH phenotype. A point mutation was detected in the T-3-binding domain of the TR beta gene. It resulted in replacement of the normal cysteine-446 with an arginine (C446R) that has not been previously reported. The clinical characteristics of this family are similar to those reported in other families with RTH, name ly goiter, tachycardia, and learning disabilities. Thyroid function te sts are also typical of other subjects with RTH. The mean values (+/-S D) in untreated affected subjects compared to those in unaffected fami ly members were: free T-4 index, 250 +/- 21 us. 108 +/- 13; total T-3, 4.3 +/- 0.4 us. 2.4 +/- 0.4 nmol/L; and TSH, 4.5 +/- 1.1 vs. 2.4 +/- 1.1 mU/L. DNA samples from 18 family members were screened for the TR beta mutation, which results in the loss of a BsmI restriction site, a nd each of the 11 subjects with abnormal thyroid function tests were h eterozygous for the mutant allele. The mutant TR beta expressed in Cos -I cells did not bind T-3 (K-6 of C446R/wild-type, <0.05). T-3 at a co ncentration up to 100 nmol/L failed to enhance the transactivation of a reporter gene, and the mutant receptor inhibited the T-3-mediated tr anscriptional activation of the wild-type TR beta.