GENETIC-ANALYSIS OF 29 KINDREDS WITH GENERALIZED AND PITUITARY RESISTANCE TO THYROID-HORMONE - IDENTIFICATION OF 13 NOVEL MUTATIONS IN THE THYROID-HORMONE RECEPTOR-BETA GENE

Resistance to thyroid hormone (RTH), with elevated serum free thyroid hormones and nonsuppressed thyrotropin levels, is either relatively as ymptomatic, suggesting a generalized disorder (GRTH) or associated wit h thyrotoxic features, indicating possible selective pituitary resista nce (PRTH). 20 GRTH and 9 PRTH cases, sporadic or dominantly inherited , were analyzed. Affected individuals were heterozygous for single nuc leotide substitutions in the thyroid hormone receptor beta gene, excep t for a single case of a seven nucleotide insertion. With one exceptio n, the corresponding 13 novel and 7 known codon changes localized to a nd extended the boundaries of two mutation clusters in the hormone-bin ding domain of the receptor. 15 kindreds shared 6 different mutations, and haplotype analyses of the mutant allele showed that they occurred independently. The majority (14 out of 19) of the recurrent but a min ority (1 out of 10) of unique mutations were transitions of CpG dinucl eotides. Mutant receptor binding to ligand was moderately or severely impaired and did not correlate with the magnitude of thyroid dysfuncti on. There was no association between clinical features and the nature or location of a receptor mutation. These observations suggest that GR TH and PRTH are phenotypic variants of the same genetic disorder, whos e clinical expression may be modulated by other non-mutation-related f actors.