A circulating, biologically inactive thyrotropin caused by a mutation in the beta subunit gene

Geraldo Medeiros-Neto, Demetrios T. Herodotou, Sabitha Rajan, Sitara Kommareddi, Luiz De Lacerda, Romolo Sandrini, Margaret C.S. Boguszewski, Anthony N. Hollenberg, Sally Radovick, Fredric E. Wondisford

Research output: Contribution to journalArticlepeer-review

101 Scopus citations


Mutation of a critical carboxy-terminal cysteine residue (C105V) in the thyrotropin-β (TSH-β) subunit gene was found in two related families with central hypothyroidism. Affected patients had low thyroid hormone levels and radioactive iodine uptake in the thyroid gland associated with measurable serum TSH. Thyrotropin-releasing hormone-stimulated TSH secretion did not increase thyroid hormone production in these patients as compared to their unaffected siblings, suggesting that the mutant TSH was biologically inactive in vivo. Recombinant TSH harboring this mutation was confirmed to be biologically inactive in an in vitro bioassay. Based on crystallographic structure of chorionic gonadotropin, a disulfide bond between C19 and C105 in the TSH-β subunit is predicted to form the 'buckle' of a 'seat belt' that surrounds the common α subunit and maintains the conformation and bioactivity of the hormone. This natural mutation of the TSH-β subunit confirms the importance of the seat belt in the family of pituitary and placental glycoprotein hormones.

Original languageEnglish (US)
Pages (from-to)1250-1256
Number of pages7
JournalJournal of Clinical Investigation
Issue number5
StatePublished - Mar 1 1996
Externally publishedYes


  • central hypothyroidism
  • gene mutation
  • pituitary
  • thyrotropin β subunit

ASJC Scopus subject areas

  • Medicine(all)


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