Two novel mutations in the thyrotropin (TSH) receptor gene in a child with resistance to TSH

R. J. Clifton-Bligh, J. W. Gregory, M. Ludgate, R. John, L. Persani, C. Asteria, P. Beck-Peccoz, V. K K Chatterjee

Research output: Contribution to journalArticle

Abstract

The TSH receptor is a G protein-coupled receptor that mediates the effects of TSH in thyroid development, growth, and synthetic function. We report here that a child with features of TSH resistance, including markedly increased serum TSH concentrations and low normal thyroid hormone levels, is a compound heterozygote for two novel mutations in the TSH receptor gene. One allele has a G to A transition corresponding to an arginine to glutamine change at codon 199 (R109Q) in the extracellular domain of the receptor. The other allele has a G to A transition corresponding to a premature termination codon at tryptophan 546 (W546X) in the fourth transmembrane segment. Each parent is heterozygous for one mutation, and both parents have normal thyroid function. Cells transiently transfected with the R109Q mutant exhibited reduced membrane binding of [125I]TSH and impaired signal transduction in response to TSH. In contrast, the W546X mutant was nonfunctional, with negligible membrane radioligand binding. Our findings indicate that a single normal TSH receptor allele is sufficient for normal thyroid function, but that the compound abnormality in the proband leads to TSH resistance.

Original languageEnglish
Pages (from-to)1094-1100
Number of pages7
JournalJournal of Clinical Endocrinology and Metabolism
Volume82
Issue number4
DOIs
Publication statusPublished - 1997

ASJC Scopus subject areas

  • Biochemistry
  • Endocrinology, Diabetes and Metabolism

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    Clifton-Bligh, R. J., Gregory, J. W., Ludgate, M., John, R., Persani, L., Asteria, C., Beck-Peccoz, P., & Chatterjee, V. K. K. (1997). Two novel mutations in the thyrotropin (TSH) receptor gene in a child with resistance to TSH. Journal of Clinical Endocrinology and Metabolism, 82(4), 1094-1100. https://doi.org/10.1210/jc.82.4.1094