A novel point mutation in cluster 3 of the thyroid hormone receptor beta gene (P247L) causing mild resistance to thyroid hormone

Resistance to thyroid hormone (RTH), a syndrome characterized by variable t issue hyposensitivity to thyroid hormone (TH), is linked to mutations in th e thyroid hormone receptor (TR) beta gene. We report a new family with a he retofore unreported mutation, P247L. The proposita, a 31-year-old female, p resented with goiter and palpitations. RTH was suspected because of elevate d serum free thyroxine (FT4) level with a normal thyrotropin (TSH). Sequenc ing the TR beta gene revealed a mutation causing replacement of a proline a t position 247 with leucine. Seven family members were heterozygous for the mutation, two of whom also had evidence of autoimmune thyroid disease. The mutant TR beta had a Ka for triiodothyronine (T-3) 30% that of the wild-ty pe TR beta, approximately a threefold reduction in T-3-induced transactivat ion and a low level dominant negative activity when tested with a positivel y regulated reporter gene. lit vivo sensitivity to TH was evaluated in thre e affected subjects by measurement of the responses to graded doses of levo triiodothyronine (LT3). Peak TSH responses to TRH were reduced and were not completely suppressed at even the highest dose of LT3, (0.9, 0.2, and 0.2, compared to <0.01 mu U/mL in unaffected controls), confirming pituitary re sistance to TH in all three subjects. In contrast, peripheral tissues respo nded variably to LT3: serum cholesterol decreased in all by 15%-25%, serum creatine kinase decreased by 15% in two subjects and increased 35% in anoth er, but serum ferritin and sex hormone-binding globulin increased in only o ne of the three affected individuals that were tested. Basal metabolic rate and sleeping pulse did not change in three and two individuals, respective ly. Hyporesponsiveness to exogenous TH established the clinical diagnosis o f RTH in one member of the family with a mutant TR beta but normal tests of thyroid function at baseline. Three affected subjects had an axis I diagno sis of major depression but had Wechsler Intelligence Scale for Children, I II (WISC-III) full-scale IQs (FSIQs) in the normal range. This novel TR bet a mutation is associated with a realtively mild RTH. Results of responses t o LT3 underscore the variable phenotype of RTH.