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The proposed mechanisms of RTH are not mutually exclusive. In fact, there is considerable experimental evidence that many if not all of these complex receptor interactions with elements of the transcriptional unit are involved in RTH. Several aspects of RTH remain unclear, in particular on a clinical level. We still do not completely understand the seeming paradox of a tight distribution of receptor mutations and wide variability in phenotypic presentation. The discovery that many of the RTH receptors have defects in corepressor interaction makes it tempting to speculate that the variability in RTH phenotype within kindreds is secondary to differences in corepressor expression. These issues may be better understood as research further proceeds into cofactors and their control of transcription. We also need better tools to determine thyroid status at a peripheral level. Basal metabolic rate, serum measurement of thyroid-responsive gene products, echocardiographic techniques, and other clinical measures have for the most part been unhelpful in determining thyroid status of specific organ systems. Consequently, therapeutic interventions for RTH are directed toward normalizing biochemical indices of thyroid homeostasis, without really knowing whether these efforts correct imbalances within crucial tissues. These studies, and the more widespread investigation of hormone receptor action in general, are moving at a breathtaking pace, and there is a keen interest in applying these principals to understanding the pathophysiologic mechanism of a variety of diseases.

Generalized thyroid hormone resistance (GTHR) is a disorder of thyroid hormone action that we have previously shown to be tightly linked to one of the two thyroid hormone receptor genes, c-erbA beta, in a single kindred, A. We now show that in two other kindreds, B and D, with differing phenotypes, there is also linkage between c-erbA beta and GTHR. The combined maximum logarithm of the odds score for all three kindreds at a recombination fraction of 0 was 5.77. In vivo studies had shown a triiodothyronine (T3)-binding affinity abnormality in nuclear receptors of kindred A, and we therefore investigated the defect in c-erbA beta in this kindred by sequencing a major portion of the T3-binding domain in the 3'-region of fibroblast c-erbA beta cDNA and leukocyte c-erbA beta genomic DNA. A base substitution, cytosine to adenine, was found at cDNA position 1643 which altered the proline codon at position 448 to a histidine. By allelic-specific hybridization, this base substitution was found in only one allele of seven affected members, and not found in 10 unaffected members of kindred A, as expected for a dominant disease. Also, this altered base was not found in kindreds B or D, or in 92 random c-erbA beta alleles. These results and the fact that the mutation is predicted to alter the secondary structure of the crucial T3-binding domain of the c-erbA beta receptor suggest this mutation is an excellent candidate for the genetic cause of GTHR in kindred A. Different mutations in the c-erbA beta gene are likely responsible for the variant phenotypes of thyroid hormone resistance in kindreds B and D.

Multiple cDNAs belonging to the c-erbA gene family encode proteins that bind T3 with high affinity. However, the biological functions of these multiple thyroid hormone receptors have not yet been clarified. Generalized thyroid hormone resistance (GTHR) refers to a human syndrome characterized by tissue refractoriness to the action of thyroid hormones; several studies have suggested quantitative or qualitative defects in T3 binding to nuclear receptors in certain kindreds. To investigate the biological functions of the c-erbA genes, c-erbA alpha and c-erbA beta, we tested the hypothesis that an abnormal c-erbA gene product is present in GTHR by examining these genes in members of one kindred. Restriction enzyme analysis failed to identify an abnormal pattern in affected individuals suggesting no rearrangements or large deletions. However, we demonstrated that the gene conferring the GTHR phenotype is tightly linked to the c-erbA beta locus on chromosome 3. This linkage strongly suggests that the c-erbA beta gene is important in man as a thyroid hormone receptor and identifies a putative c-erbA beta mutant phenotype with central nervous system, pituitary, liver, metabolic, and growth abnormalities.