Dominant inheritance of resistance to thyroid hormone not linked to defects in the thyroid hormone receptor α or β genes may be due to a defective cofactor

Roy E. Weiss, Yoshitaka Hayashi, Takashi Nagaya, Kevin J. Petty, Yoshiharu Murata, Hakan Tunca, Hisao Seo, Samuel Refetoff

Research output: Contribution to journalArticlepeer-review

97 Scopus citations


Resistance to thyroid hormone (RTH) is an inherited syndrome of reduced tissue responsiveness to thyroid hormone. To date, all individuals expressing the RTH phenotype have been found to harbor mutations in the thyroid hormone receptor β (TRβ) gene that impair T3-mediated function. We describe a unique family in which the dominantly inherited RTH is not associated with abnormalities in the TRβ or TRα genes, as determined by gene sequencing and linkage analysis. However, affected family members manifest a severe form of RTH, with reduced responses of thyrotrophs and peripheral tissues requiring 8- to 10-fold the normal replacement doses of L-T4 and L-T3. No other endocrine abnormalities were detected. The defect developed de novo in the proposita and was transmitted to her two children of unrelated fathers. As cultured fibroblasts from the proposita responded poorly to T3 despite a normal concentration of TR, other abnormalities in the mediation of T3 action were sought. Nucleotide sequences of the TSHβ promoter, containing thyroid hormone response elements, and TR-interacting protein 1 were normal. Nuclear extracts (NE) of cultured skin fibroblasts from affected individuals of this family were tested for their interaction with normal TRβ and thyroid hormone response elements by the electrophoretic mobility shift assay. NE from the proposita showed a strong additional band compared to NEs from normal individuals and patients with RTH caused by TRβ mutations or deletion. Far Western analysis of NE from the affected daughter hybridized with labeled TRβ demonstrated an additional band that was not seen in NEs from a normal control or patients with TRβ gene defects. It is concluded that the etiology of RTH is not confined to abnormalities in the TRβ gene. An abnormal cofactor with a specific function in the regulation of thyroid hormone action is probably involved in the expression of the RTH phenotype in this family.

Original languageEnglish (US)
Pages (from-to)4196-4203
Number of pages8
JournalJournal of Clinical Endocrinology and Metabolism
Issue number12
StatePublished - 1996
Externally publishedYes

ASJC Scopus subject areas

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


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