Pathophysiology and Mouse Models of Thyroid Hormone Resistance Syndromes: A Focus on the Brain

Thyroid hormone receptor mutations cause syndromes of resistance to the action of thyroid hormones (RTH) with autosomal dominant inheritance. Mutations in the THRA gene, encoding TRα1 and TRα2, cause RTHα, and those in THRB, encoding TRβ1 and TRβ2, cause RTHβ. In RTHα, relatively mild changes in circulating thyroid hormones coexist with signs of congenital hypothyroidism. In contrast, in RTHβ, TSH levels are not suppressed despite elevated thyroid hormone levels. The mutant receptors have low or no T3-induced activation and display dominant negative activity, inhibiting the wild-type receptors’ transcriptional activation. This chapter describes the main characteristics of RTH, including a discussion of the mouse models of the disorder, with an emphasis on neural aspects.