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Soluble Ecto-Domain Mutant of Thyrotropin (TSH) Receptor Incapable of Binding TSH Neutralizes the Action of Thyroid-Stimulating Antibodies from Graves’ Patients¹

Division of Reproductive Biology (Y.O., S.-G.L., A.J.W.H), Department of Gynecology/Obstetrics, Stanford University School of Medicine, Stanford, California 94305; Department of Pediatrics (J.S.D.), University of Texas Medical Branch, Galveston, Texas 77555; and Division of Endocrinology, Department of Medicine (C.W.), Harbor-UCLA Medical Center, Torrance California 90502

Address all correspondence and requests for reprints to: Aaron J. W. Hseuh, M.D., Stanford University School of Medicine, Department of Gynecology/Obstetrics, 300 Pasteur Drive, Stanford, California 94305-5317.

A soluble form of the amino-terminal extracellular (ecto-) domain of the human TSH receptor was generated. This protein was capable of binding TSH and autoimmune antibodies found in Graves’ patients. A deletion mutant of the ectodomain lacking nine amino acids in the C-terminal region lost its ability to interact with TSH but retained binding to Graves’ IgGs. In cells expressing recombinant TSH receptors, cotreatment with the mutant protein blocked the cAMP production induced by stimulating antibodies from all Graves’ patients tested but was without effect on TSH action. The ability to dissociate the actions of TSH and Graves’ IgGs provides a tool with which to study the mechanisms underlying Graves’ disease and the possibility of neutralizing the undesirable effects of thyroid-stimulating antibodies without altering the normal responses to TSH.

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