A new point mutation (C446R) in the thyroid hormone receptor-β gene of a family with resistance to thyroid hormone

Roy E. Weiss, Brent Chyna, P. Barton Duell, Yoshitaka Hayashi, Thongkum Sunthornthepvarakul, Samuel Refetoff

Research output: Contribution to journalComment/debatepeer-review

17 Scopus citations


Resistance to thyroid hormone (RTH) is a condition of impaired end-organ responsiveness to thyroid hormone characterized by goiter and elevated thyroid hormone levels with an inappropriately normal TSH. RTH has been associated with mutations in the thyroid hormone receptor-β (TRβ) gene. We report studies carried out in 21 members of a family (F119), 12 of whom exhibited the RTH phenotype. A point mutation was detected in the T3- binding domain of the TRβ gene. It resulted in replacement of the normal cysteine-446 with an arginine (C446R) that has not been previously reported. The clinical characteristics of this family are similar to those reported in other families with RTH, namely goiter, tachycardia, and learning disabilities. Thyroid function tests are also typical of other subjects with RTH. The mean values (±SD) in untreated affected subjects compared to those in unaffected family members were: free T4 index, 250 ± 21 vs. 108 ± 13; total T3, 4.3 ± 0.4 vs. 2.4 ± 0.4 nmol/L; and TSH, 4.5 ± 1.1 vs. 2.4 ± 1.1 mU/L. DNA samples from 18 family members were screened for the TRβ mutation, which results in the loss of a BsmI restriction site, and each of the 11 subjects with abnormal thyroid function tests were heterozygous for the mutant allele. The mutant TRβ expressed in Cos-I cells did not bind T3 (K(a) of C446R/wild-type, <0.05). T3 at a concentration up to 100 nmol/L failed to enhance the transactivation of a reporter gene, and the mutant receptor inhibited the T3-mediated transcriptional activation of the wild- type TRβ.

Original languageEnglish (US)
Pages (from-to)1253-1256
Number of pages4
JournalJournal of Clinical Endocrinology and Metabolism
Issue number5
StatePublished - May 1994

ASJC Scopus subject areas

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


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