2 NOVEL MUTATIONS IN THE THYROTROPIN (TSH) RECEPTOR GENE IN A CHILD WITH RESISTANCE TO TSH

The TSH receptor is a G protein-coupled receptor that mediates the eff ects of TSH in thyroid development, growth, and synthetic function. We report here that a child with features of TSH resistance, including m arkedly increased serum TSH concentrations and low normal thyroid horm one 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 extracell ular domain of the receptor. The other allele has a G to A transition corresponding to a premature termination codon at tryptophan 546 (W546 X) in the fourth transmembrane segment. Each parent is heterozygous fo r one mutation, and both parents have normal thyroid function. Cells t ransiently transfected with the R109Q mutant exhibited reduced membran e binding of[I-125]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 nor mal TSH receptor allele is sufficient for normal thyroid function, but that the compound abnormality in the proband leads to TSH resistance.