Differential expression of mutant and normal beta T3 receptor alleles in kindreds with generalized resistance to thyroid hormone.

Thyroid hormone resistance (THR) is primarily an autosomal dominant inherited disease characterized by resistance of pituitary and peripheral tissues to the action of thyroid hormone. We investigated whether the heterogeneous phenotypic features that occur not only among kindreds but also within the same kindred might be due to the expression of differing ratios of mutant and normal receptors in tissues. Using an allele-specific primer extension method, we determined the relative expression of normal and mutant mRNAs from the fibroblasts of affected and unaffected members of two kindreds with TRH: A-H and N-N. While two affected members of A-H, as expected, had nearly equal amounts of normal and mutant hTR beta mRNA, two other members had mutant mRNA levels that accounted for at least 70% of the hTR beta mRNA. Phenotypic variability within and between kindreds with generalized resistance to thyroid hormone GRTH may be due to this differential expression of the mutant and wild type mRNA. Furthermore, when several clinical parameters of THR were compared in several affected members from two kindreds with GRTH, we found that two cases in one kindred exhibited a high mutant-to-normal hTR beta ratio and had considerably more bone resistance during their development. In certain kindreds with THR, differing ratios of normal and mutant hTR receptors may be age and growth related and may account for the reported attenuation of phenotypic symptoms with age.

Identification of a novel mutation in the gene encoding the beta-triiodothyronine receptor in a patient with apparent selective pituitary resistance to thyroid hormone.

OBJECTIVE: We investigated whether the first patient (L-F3) reported as having selective pituitary resistance had a mutation in the hTR beta gene. We compared the clinical parameters of this case with those of patients with generalized resistance to thyroid hormone. DESIGN: The patient, L-F3, was part of a study at the NIH to identify mutations by sequencing the hTR beta gene in kindreds with thyroid hormone resistance. The clinical data of L-F3 as well as patients with generalized resistance to thyroid hormone were compared and analysed retrospectively. MEASUREMENT: We amplified by the polymerase chain reaction and then sequenced exons 5 to 10 of the hTR beta gene in L-F3 and a normal control. Upon finding the mutation in L-F3, we measured the affinity constant of this mutated hTR beta receptor. Criteria developed previously were used to assess tissue responsiveness to thyroid hormone of L-F3. RESULTS: We identified a C to T transition at base 1297 in codon 333 of the hTR beta gene in the first patient (L-F3) reported as having apparent selective pituitary resistance. This base substitution resulted in more than a four-fold decrease in T3-binding affinity for the hTR beta 1 receptor. The mutation of L-F3 occurred in the dimerization domain of exon 9, a region where the majority of mutations of kindreds with generalized thyroid hormone resistance have been found. Furthermore, the nucleotide substitution at base 1297 found in the apparent selective pituitary resistant case, L-F3, was the same as in an unrelated patient (K-T3) with generalized resistance to thyroid hormone. As a result, we compared the clinical parameters of both patients and found that they had similar patterns of resistance in several tissues. Besides the bone resistance present in both kindreds, the apparent selective pituitary resistance case also had liver and neuromuscular resistance. CONCLUSIONS: These findings suggest that apparent selective pituitary resistance and generalized resistance to thyroid hormone are not qualitatively different syndromes. Nevertheless, identification of selective pituitary resistance is a useful clinical distinction since such patients with clinical and biochemical features of hyperthyroidism appear to benefit from reduction in serum thyroid hormone concentrations. In contrast, patients with more conventional forms of thyroid hormone resistance require no treatment or may benefit from increased concentrations of thyroid hormone.