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A De Novo Mutation in an Already Mutant Nucleotide of the Thyroid Hormone Receptor ß Gene Perpetuates Resistance to Thyroid Hormone

Departments of Medicine (J.L.-A., X.-H.L., R.N.C., J.P., R.E.W., S.R.), Pediatrics (S.R.), and Human Genetics (A.M.D.), and Committee on Genetics (S.R.), The University of Chicago, Chicago, Illinois 60637; Clinical Genetic Unit (A.V.), Hôpital Robert Debré, 75019 Paris, France; and Pediatric Endocrinology (M.-C.L.), Hôpital de la Citadelle, 4000 Liège, Belgium

Address all correspondence and requests for reprints to: Samuel Refetoff, University of Chicago, MC 3090, 5841 South Maryland Avenue, Chicago, Illinois 60637. E-mail: refetoff{at}uchicago.edu.

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) ß gene. Mutations are mostly located in the ligand-binding domain of the TRß, decreasing T₃ binding to the mutant TRß molecule, which in turn interferes with the function of the wild-type (WT) TR. A total of 122 different TRß gene mutations have been identified so far, with 46 occurring in more than one family. We now report a family with two novel TRß 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 T₄ and T₃ 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 TRß 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 TRßs with the wild-type TRß showed a potent dominant negative effect. Large amounts of T₃ were required to dissociate homodimers of the mutant TRß bound to DNA. In addition, and in contrast to other mutant TRßs with severe T₃-binding defects, homodimer release failed to recruit the steroid receptor coactivator. No defects in heterodimerization with retinoid X receptor- 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.

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