title: A novel germline mutation in the TSH receptor gene causes non-autoimmune autosomal dominant hyperthyroidism.
abstract: OBJECTIVE
  Clinical and genetic investigations were undertaken in a case of familial hyperthyroidism, with onset of thyrotoxic symptoms varying between childhood/adolescence.
  
  
  METHODS
  Automatic sequence analysis was carried out of the TSH receptor (TSHR) gene. Functional studies were undertaken of mutant TSHR in transient expression experiments in COS-7 cells including the evaluation of cAMP accumulation and of protein expression by flow cytometry, as well as the calculation of specific constitutive activity (SCA).
  
  
  RESULTS
  In four affected cases, the age of onset of thyrotoxic manifestations of non-autoimmune origin varied between 5 and 18 years. The disease transmission was typically autosomal dominant. TSHR gene sequence revealed the presence of a germline heterozygous substitution at codon 597 leading to the novel mutation V597F. This residue is located in the 5th transmembrane domain of the receptor protein in a critical region for membrane targeting and signal transduction. Functional studies of the V597F mutant indicate an 11-fold increase in SCA, associated with a reduction in receptor protein expression 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.
authors.affiliation: Institute of Endocrine Sciences, University of Milan, Istituto Auxologico Italiano IRCCS, Via Ariosto 13, 20145 Milan, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Alberti
authors.forename: M C
authors.initials: MC
authors.lastname: Proverbio
authors.forename: S
authors.initials: S
authors.lastname: Costagliola
authors.forename: G
authors.initials: G
authors.lastname: Weber
authors.forename: P
authors.initials: P
authors.lastname: Beck-Peccoz
authors.forename: G
authors.initials: G
authors.lastname: Chiumello
authors.forename: L
authors.initials: L
authors.lastname: Persani
mesh_terms: D000818:Animals; D019556:COS Cells; D002675:Child, Preschool; D003001:Cloning, Molecular; D000242:Cyclic AMP / Q000378:metabolism; D004247:DNA / Q000097:blood; D005260:Female; D005434:Flow Cytometry; D015870:Gene Expression; D018095:Germ-Line Mutation; D006579:Heterozygote; D006801:Humans; D006980:Hyperthyroidism / Q000235:genetics*; D016297:Mutagenesis, Site-Directed; D010375:Pedigree; D011989:Receptors, Thyrotropin / Q000235:genetics*; D013972:Thyrotropin / Q000494:pharmacology; D014162:Transfection
chemical_list: D011989:Receptors, Thyrotropin; D013972:Thyrotropin; D004247:DNA; D000242:Cyclic AMP