Two consecutive nucleotide substitutions resulting in the T3 receptor beta gene resulting in an 11-amino acid truncation in a patient with generalized resistance to thyroid hormone.

We identified unusual mutations in the T3 receptor (TR) beta gene in a 6-year-old Japanese girl with generalized resistance to thyroid hormone. Two consecutive base substitutions, T to A and C to A at nucleotide positions 1637 and 1638, respectively, changed the 451st codon coding for Phe(TTC) to stop codon (TAA), resulting in an 11-amino acid carboxyl(C)-terminus truncation. The patient was a heterozygote. Western blotting using an anti-TR antibody demonstrated the truncated receptor protein. The patient showed severe mental retardation (IQ41), disturbance in speech development, and attention deficit hyperactivity disorder. Thyroid functional status by clinical evaluation was considered within the normal range in spite of high serum thyroid hormone levels (T4 725.9 nmol/l, T3 12.7 nmol/l, FT4 166.0 pmol/l). TSH increased from 0.6 to 24 mU/L after TRH (150 micrograms) injection. TSH secretion as well as 123I-uptake was suppressed only partially by T3 (75 micrograms/day for a week). Close examination of thyroid functions and TR beta gene analysis were not possible in the family, except for paternal grandmother and one of her two sisters who showed no abnormality. The patient's truncated TR beta showed very low T3 binding activity (Ka = 0.1 x 10-10 M), transcriptional activity, and a very strong dominant negative effect. When co-expressed with wild-type TR beta at the molar ratio 1:1 in CV-1 cells, the mutant receptor inhibited the wild-type TR beta transcriptional activity by 74% at 10 nM T3. Even 1 microM T3 could not normalize these impaired functions.