[Genetic analysis of hormone resistance]

Thyroid hormone resistance is a syndrome defined as impaired tissue response to thyroid hormone which would be excessive under normal circumstances. Although it has long been speculated that this defect was caused by an abnormality at the site of the nuclear receptor for thyroid hormone, isolation of complementary DNA encoding thyroid hormone receptors has only recently enabled us to directly examine this hypothesis. Thyroid hormone receptors are coded on two separate genes, THRA and THRB. Both genes give rise to multiple receptor subtypes through alternative splicing or different usage of promoters. Tight linkage between THRB locus and resistant phenotype was demonstrated in one affected family, and subsequently, more than 30 genetic abnormalities of the THRB gene were isolated. No abnormalities have been demonstrated on the THRA gene. Denaturing gradient gel electrophoresis was used to screen abnormalities on the THRB gene of affected families, and the results also strongly supported the hypothesis that thyroid hormone resistance is caused by an abnormal THRB gene. Molecular analysis of thyroid hormone resistance will facilitate understanding of the pathophysiology of this syndrome and the molecular mechanism of thyroid hormone action.