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Two Novel Mutations in the Thyrotropin (TSH) Receptor Gene in a Child with Resistance to TSH¹

Department of Medicine, University of Cambridge, Addenbrooke’s Hospital (R.J.C.-B., V.K.K.C.), Cambridge, United Kingdom CB2 2QQ; the Departments of Child Health (J.W.G.), Pathology (M.L.), and Medical Biochemistry (R.J.), University Hospital of Wales, Cardiff, United Kingdom CF4 4XW; and the Institute of Endocrine Sciences, University of Milan, Ospedale Maggiore, IRCCS and Centro Auxologico Italiano IRCCS (L.P., C.A., P.B.-P.), Milan, Italy

Address all correspondence and requests for reprints to: Dr. V. K. K. Chatterjee, Department of Medicine, University of Cambridge, Level 5, Addenbrooke’s Hospital, Hills Road, Cambridge, United Kingdom CB2 2QQ.

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 109 (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.

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