A de novo mutation in an already mutant nucleotide of the thyroid hormone receptor β gene perpetuates resistance to thyroid hormone

Joaquin Lado-Abeal, Alexandra M. Dumitrescu, Xiao Hui Liao, Ronald N. Cohen, Joachim Pohlenz, Roy E. Weiss, Marie Christine Lebrethon, Alain Verloes, Samuel Refetoff

Research output: Contribution to journalArticlepeer-review

16 Scopus citations


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

Original languageEnglish (US)
Pages (from-to)1760-1767
Number of pages8
JournalJournal of Clinical Endocrinology and Metabolism
Issue number3
StatePublished - Mar 2005
Externally publishedYes

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Biochemistry
  • Endocrinology
  • Clinical Biochemistry
  • Biochemistry, medical


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