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

Resistance to thyroid hormone (RTH), a syndrome characterized by variable tissue hyposensitivity to thyroid hormone (TH), is linked to mutations in the thyroid hormone receptor (TR) β gene. We report a new family with a heretofore unreported mutation, P247L. The proposita, a 31- year-old female, presented with goiter and palpitations. RTH was suspected because of elevated serum free thyroxine (FT₄) level with a normal thyrotropin (TSH). Sequencing the TRβ gene revealed a mutation causing replacement of a proline at position 247 with leucine. Seven family members were heterozygous for the mutation, two of whom also had evidence of autoimmune thyroid disease. The mutant TRβ had a Ka for triiodothyronine (T₃) 30% that of the wild-type TRβ, approximately a threefold reduction in T₃-induced transactivation and a low level dominant negative activity when tested with a positively regulated reporter gene. In vivo sensitivity to TH was evaluated in three affected subjects by measurement of the responses to graded doses of levotriiodothyronine (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 μU/mL in unaffected controls), confirming pituitary resistance to TH in all three subjects. In contrast, peripheral tissues responded variably to LT₃: serum cholesterol decreased in all by 15%-25%, serum creatine kinase decreased by 15% in two subjects and increased 35% in another, but serum ferritin and sex hormone-binding globulin increased in only one of the three affected individuals that were tested. Basal metabolic rate and sleeping pulse did not change in three and two individuals, respectively. Hyporesponsiveness to exogenous TH established the clinical diagnosis of RTH in one member of the family with a mutant TRβ but normal tests of thyroid function at baseline. Three affected subjects had an axis I diagnosis of major depression but had Wechsler Intelligence Scale for Children, III (WISC-III) full-scale IQs (FSIQs) in the normal range. This novel TRβ mutation is associated with a relatively mild RTH. Results of responses to LT₃ underscore the variable phenotype of RTH.