THE RELATIVE EXPRESSION OF MUTANT AND NORMAL THYROID-HORMONE RECEPTORGENES IN PATIENTS WITH GENERALIZED RESISTANCE TO THYROID-HORMONE DETERMINED BY ESTIMATION OF THEIR SPECIFIC MESSENGER-RIBONUCLEIC-ACID PRODUCTS

Generalized resistance to thyroid hormone (GRTH), is a syndrome of red uced tissue responsiveness to thyroid hormone. So far, mutations linke d to GRTH have been only detected in the hormone-binding domain of the human thyroid hormone receptor (hTR)-beta gene. Although there is no doubt that these mutations result in abnormal hTRs, there is a conspic uous lack of correlation between the severity of clinical manifestatio ns and the degree of functional impairment of the mutant hTRs. In this work we examined whether variable expression of mutant genes relative to the normal genes could explain the observed discrepancies. The rel ative amounts of mutant and normal hTRbeta and normal hTRalpha messeng er RNAs in fibroblasts from normal subjects and those from individuals with GRTH were estimated by coamplification of their complementary DN A products. Heterozygous subjects with GRTH from two families manifest ing differences in the severity of clinical manifestations expressed e qually both normal and mutant hTRbeta alleles. Furthermore, there was no compensatory increase in the expression of the normal hTRalpha gene in these individuals nor in fibroblasts from members of a third famil y with homozygous deletion of the hTRbeta gene. In vitro treatment wit h thyroid hormone did not affect the results. It is concluded that the apparent discrepancies between the functional impairment of the mutan t hTRs and the clinical manifestations of GRTH are not due to quantita tive differences in the expression of the normal or mutant hTR genes b ut more likely to variations in the interactions of the mutant hTRs wi th the normal hTRbeta, hTRalpha and nuclear stabilization factors.