These findings indicate that, although mutations at Met256-TRα1/Met310-TRβ1 residues preserve T4 binding to mutant receptor proteins, this property is not sufficient to prevent patients from developing features of RTH, implying that the phenotype of RTH is linked primarily to defective T3 rather than T4 binding by mutant TRs. This evidence concerns the gene CD4 and thyroid hormone resistance syndrome.