Five new families with resistance to thyroid hormone not caused by mutations in the thyroid hormone receptor β gene

Joachim Pohlenz, Roy E. Weiss, Paolo E. Macchia, Silvana Pannain, Ip Tim Lau, Herbert Ho, Samuel Refetoff

Research output: Contribution to journalArticlepeer-review

94 Scopus citations


Resistance to thyroid hormone (RTH) is a syndrome of variable tissue hyposensitivity to TH. In 191 families, the RTH phenotype has been linked to mutations located in the ligand-binding or hinge domains of the TH receptor (TR) β gene. The defective TRβ molecules interfere with the function of the normal TRs to produce dominantly inherited RTH. Of the 65 families with RTH studied in our laboratory, 59 had mutations in the mutagenic region of the TRβ gene that encompasses exons 7-10. Isolation of a TRβ PAC (P1 derived artificial chromosome) clone provided the intronic sequences necessary to amplify and sequence the entire TRβ gene from genomic DNA. Not a single nucleotide substitution, deletion, or insertion was found in all coding and noncoding TRβ1- and TRβ2-specific and common exons of the five families with RTH reported herein. Furthermore, linkage analysis using polymorphic markers excluded involvement of the TRβ and TRα genes in two and three of the five families, respectively. The phenotype of RTH in patients without TRβ gene defects was not different from that in patients with RTH due to TRβ gene mutations in terms of clinical presentation and reduced responsiveness of the pituitary and peripheral tissues to TH. However, the degree of thyrotroph hyposensitivity to TH appeared to be among the more severe, similar to that of patients with mutant TRβs that have more than 50-fold reduction of T3 binding affinity and strong dominant negative effect. In these five families and another with non-TRα/non-TRβ RTH, previously identified in our laboratory, evidence for dominant inheritance was secured in two families, and the appearance of a new defect or recessive inheritance was found in the remaining four families. RTH without a structural TRβ defect occurs in about 10% of families expressing the classic phenotype of TH hyposensitivity, and TRβ and TRα gene involvement has been excluded in 5%. We postulate that a cofactor that interacts with TR is potentially responsible for the manifestation of RTH in these families. As affected subjects are not infertile, the high prevalence of putative neomutations and the low rate of transmission in this non-TR form of RTH may be due to reduced survival of embryos harboring the defect.

Original languageEnglish (US)
Pages (from-to)3919-3928
Number of pages10
JournalJournal of Clinical Endocrinology and Metabolism
Issue number11
StatePublished - 1999
Externally publishedYes

ASJC Scopus subject areas

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


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