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Resistance to thyroid hormone (RTH) is a syndrome of reduced sensitivity to thyroid hormone, most commonly caused by mutations in the thyroid hormone receptor (TR) beta gene. Mutations are mostly located in the ligand-binding domain of the TRbeta, decreasing T(3) binding to the mutant TRbeta molecule, which in turn interferes with the function of the wild-type (WT) TR. A total of 122 different TRbeta gene mutations have been identified so far, with 46 occurring in more than one family. We now report a family with two novel TRbeta mutations occurring in the same nucleotide. The proposita had two children from each of her two marriages. One daughter and one son from each marriage had severe RTH with free T(4) and T(3) levels 3- to 4-fold the mean normal values and unsuppressed TSH, mental retardation, and deafness. The proposita had a missense mutation (GTG to GGG) in codon 458 of the TRbeta gene, resulting in the replacement of the normal valine with glycine (V458G). Although this mutation was transmitted to her affected son, the mutated codon in her affected daughter was GAG, encoding glutamic acid (V458E). Haplotype analysis showed that this de novo mutation occurred on the already mutant allele of the proposita. Cotransfection of each of these mutant TRbetas with the wild-type TRbeta showed a potent dominant negative effect. Large amounts of T(3) were required to dissociate homodimers of the mutant TRbeta bound to DNA. In addition, and in contrast to other mutant TRbetas with severe T(3)-binding defects, homodimer release failed to recruit the steroid receptor coactivator. No defects in heterodimerization with retinoid X receptor-alpha or association with a nuclear receptor corepressor, were identified. These in vitro data are in agreement with the in vivo phenotype of severe RTH. Unique and previously unreported in human inherited diseases is the occurrence of a de novo mutation at an already mutant nucleotide. Because the occurrence by chance is extremely unlikely, it is postulated that the presence of three guanines in the sequence created by the mutant nucleotide of the proposita results in a mutagenic site prone to de novo mutation.

ADe NovoMutation in an Already Mutant Nucleotide of the Thyroid Hormone Receptor β Gene Perpetuates Resistance to Thyroid Hormone