Analysis of the TSHR gene in patients with isolated hyperthyrotropinemia

TSH receptor is a member of the leucine-rich repeat-containing G protein coupled receptors. Inactivating mutations of the TSH receptor have been detected in several cases of resistance to TSH both partial and complete. In the present study we observed 11 unrelated patients with hyperthyrotropinemia (serum TSH range: 5-24 MCUI/mL), normal free thyroid hormone levels, negative thyroid antibodies, and normal thyroid ultrasound. By direct sequencing of the TSHR gene coding regions we detected 2 different nucleotide substitutions in two families: The G>A substitution at codon 410 that results in the known inactivating mutation Asp410Asn and the T>C substitution at codon 527 that results in the variant Met527Thr, affecting a residue located in the second intracellular loop, that as far as we know has never been described. Parents' DNA analysis showed that the Asp410Asn mutation and the Met527Thr variant were carried by the maternal and the paternal allele, respectively. The variant Met527Thr was found in a female with idiopathic central precocious puberty and serum TSH levels of 12 MCUI/mL. She started therapy with L-Thyroxine and the dose was increased during the follow-up. Her father (serum TSH.levels 5.12 MCUI/mL) was clinically euthyroid and never needed therapy. In conclusion we found the new variant Met527Thr located in the second intracellular loop that could be important for the adenylate cyclase activation in receptor signalling. The variability of the phenotypical expression leads to a long term follow-up in these patients to decide the correct therapeutical approach.