SOLUBLE ECTO-DOMAIN MUTANT OF THYROTROPIN (TSH) RECEPTOR INCAPABLE OFBINDING TSH NEUTRALIZES THE ACTION OF THYROID-STIMULATING ANTIBODIES FROM GRAVES PATIENTS

A soluble form of the amino-terminal extracellular (ecto-) domain of t he human TSH receptor was generated. This protein was capable of bindi ng TSH and autoimmune antibodies found in Graves' patients. A deletion mutant of the ectodomain lacking nine amino acids in the C-terminal r egion lost its ability to interact with TSH but retained binding to Gr aves' IgGs. In cells expressing recombinant TSH receptors, cotreatment with the mutant protein blocked the cAMP production induced by stimul ating antibodies from all Graves' patients tested but was without effe ct on TSH action. The ability to dissociate the actions of TSH and Gra ves' IgGs provides a tool with which to study the mechanisms underlyin g Graves' disease and the possibility of neutralizing the undesirable effects of thyroid-stimulating antibodies without altering the normal responses to TSH.