Similarities and differences in the phenotype of members of an Italian family with hereditary non-autoimmune hyperthyroidism associated with an activating TSH receptor germline mutation

J Endocrinol Invest. 2002 Sep;25(8):696-701. doi: 10.1007/BF03345103.


Constitutively activating germline mutations of the TSH receptor (TSH-R) are considered the cause of hereditary non-autoimmune hyperthyroidism. In this study, 10 members (8 affected and 2 unaffected) of an Italian family with hereditary non-autoimmune hyperthyroidism were investigated for the presence of mutations in the TSH-R gene. The clinical features of the disease were also analyzed. PCR-amplified fragments of the TSH-R gene were obtained from genomic DNA extracted from peripheral blood leukocytes of each family member and analyzed by direct nucleotide sequencing and restriction analysis. An identical germline TSH-R mutation was detected in all the patients with hyperthyroidism but in none of the unaffected family members. The mutation was heterozygotic and determined the substitution of valine for methionine (codon 463; ATG-->GTG) in the second transmembrane domain of the TSH-R. When expressed in chinese hamster ovary (CHO) cells, the Val463 mutant TSH-R induced constitutive activation of the TSH receptor. Analysis of the clinical features of our family and those of other families with hereditary non-autoimmune hyperthyroidism, including one with the same Val463 mutation, revealed wide variability in the phenotypical expression of the disease. Our findings indicate that an activating germline mutation in the TSH-R gene plays a key role in hereditary non-autoimmune hyperthyroidism although the onset of clinical manifestations and the evolution of the disease seem to depend heavily on other factors, thus far unidentified. The absence of a clear correlation between mutant genotypes and phenotypic expression of the disease currently limits the prognostic value of genetic testing in families with hereditary non-autoimmune hyperthyroidism.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Animals
  • CHO Cells
  • Cricetinae
  • Female
  • Germ-Line Mutation* / genetics
  • Germ-Line Mutation* / physiology
  • Humans
  • Hyperthyroidism / genetics*
  • Male
  • Methionine
  • Middle Aged
  • Pedigree
  • Phenotype
  • Receptors, Thyrotropin / genetics*
  • Valine


  • Receptors, Thyrotropin
  • Methionine
  • Valine