Objective: Clinical and genetic investigations were undertaken in a case of
familial hyperthyroidism, with onset of thyrotoxic symptoms varying betwee
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.