Germline mutations in the thyrotropin receptor gene cause non-autoimmune autosomal dominant hyperthyroidism

Nat Genet. 1994 Jul;7(3):396-401. doi: 10.1038/ng0794-396.


The thyrotropin receptor (TSHR), a member of the large family of G protein-coupled receptors, controls both the function and growth of thyroid cells via stimulation of adenylyl cyclase. We report two different mutations in the TSHR gene of affected members of two large pedigrees with non-autoimmune autosomal dominant hyperthyroidism (toxic thyroid hyperplasia), that involve residues in the third (Val509Ala) and seventh (Cys672Tyr) transmembrane segments. When expressed by transfection in COS-7 cells, the mutated receptors display a higher constitutive activation of adenylyl cyclase than wild type. This new disease entity is the germline counterpart of hyperfunctioning thyroid adenomas, in which different somatic mutations with similar functional characteristics have been demonstrated.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoma / genetics
  • Adenylyl Cyclases / metabolism
  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Cell Line
  • Chlorocebus aethiops
  • Cyclic AMP / physiology
  • DNA Mutational Analysis
  • Enzyme Activation
  • Female
  • France / epidemiology
  • Genes, Dominant*
  • Humans
  • Hyperthyroidism / genetics*
  • Male
  • Models, Molecular
  • Molecular Sequence Data
  • Pedigree
  • Point Mutation*
  • Protein Conformation
  • Receptors, Thyrotropin / chemistry
  • Receptors, Thyrotropin / genetics*
  • Receptors, Thyrotropin / physiology
  • Second Messenger Systems
  • Thyroid Neoplasms / genetics
  • Transfection


  • Receptors, Thyrotropin
  • Cyclic AMP
  • Adenylyl Cyclases