A novel thyrotropin receptor mutation in an infant with severe thyrotoxicosis

An infant girl was born at 37 weeks gestation and found to be clinically th yrotoxic at 9 months of age. Thyroid autoantibodies were negative, and thyr oid function failed to normalize with medical treatment. The patient underw ent a total thyroidectomy. DNA obtained from her thyroid gland and leukocyt es was analyzed for thyrotropin receptor (TSHR) mutations using single stra nd conformation polymorphism and direct sequencing. A mobility shift of pol ymerase chain reaction (PCR)-amplified DNA was detected on single strand co nformation polymorphism gel. Direct sequencing identified a novel point mut ation in the fifth transmembrane domain of the TSH receptor at codon 597 (G TC to CTC), resulting in the amino acid substitution of leucine for valine. The mutation was heterozygous and germline, and was not identified in DNA from either of her parents. Expression of the V597L mutant is transiently t ransfected COS 7 cells displayed increased constitutive cyclic adenosine mo nophosphate (cAMP) production compared with the wild-type receptor. The mut ant is expressed at very low levels on the surface of COS cells, and its re sponse to TSH is marginal.