RESISTANCE TO THYROID-HORMONE IN SUBJECTS FROM 2 UNRELATED FAMILIES IS ASSOCIATED WITH A POINT MUTATION IN THE THYROID-HORMONE RECEPTOR-BETA GENE RESULTING IN THE REPLACEMENT OF THE NORMAL PROLINE-453 WITH SERINE

Resistance to thyroid hormone (RTH) is a condition of impaired tissue responsiveness to thyroid hormone characterized by elevated free thyro id hormone levels in serum accompanied by nonsuppressed TSH. RTH has b een associated with mutations in the thyroid hormone receptor (TR) bet a gene. We report studies carried out in 9 members of a family (F94) o f Jewish ethnic origin and a single subject of Mexican origin. All sub jects fulfilling the criteria of RTH (6 of family F94 and one of famil y F27) had the same point mutation in the T-3-binding domain on one of the two alleles of the TRP gene. This mutation resulted in the replac ement of the normal proline-453 with serine (P453S). Nevertheless, the clinical characteristics of affected members of each of the two famil ies differed as did the severity of hormonal resistance in terms of re sponses to the administration of L-T-3. Genetic studies indicate that the same mutation occurred independently in each of the two families.