A novel germline mutation in the TSH receptor gene causes non-autoimmune autosomal dominant hyperthyroidism

Objective: Clinical and genetic investigations were undertaken in a case of familial hyperthyroidism, with onset of thyrotoxic symptoms varying betwee n childhood/adolescence. Methods: Automatic sequence analysis was carried out of the TSH receptor (T SHR) gene. Functional studies were undertaken of mutant TSHR in transient e xpression experiments in COS-7 cells including the evaluation of cAMP accum ulation and of protein expression by flow cytometry, as well as the calcula tion of specific constitutive activity (SCA). Results: In four affected cases, the age of onset of thyrotoxic manifestati ons of non-autoimmune origin varied between 5 and 18 years. The disease tra nsmission was typically autosomal dominant. TSHR gene sequence revealed the presence of a germline heterozygous substitution at codon 597 leading to t he novel mutation V597F. This residue is located in the 5th transmembrane d omain of the receptor protein in a critical region for membrane targeting a nd signal transduction. Functional studies of the V597F mutant indicate an 11-fold increase in SCA, associated with a reduction in receptor protein ex pression on the cytoplasmic membrane. Conclusions: Description was made of a family with non-autoimmune autosomal dominant hyperthyroidism carrying a novel mutation of TSHR leading to the increment in specific constitutive activity. Factors that may influence the clinical expression of TSHR germline mutations are discussed.