Presence of nonfunctional thyrotropin receptor variant transcripts in retroocular and other tissues.

The TSH receptor (TSHR) has been proposed as an antigenic link between the thyroid and the orbit; TSHR transcripts have been demonstrated by other groups, one in orbital tissue and the other in orbital and dermal fibroblasts. In a previous study we were unable to demonstrate transcripts for the complete TSHR in retroocular muscle containing also fibroblasts. We now confirm this finding. A 1.3-kilobase variant of the TSHR messenger ribonucleic acid (mRNA) has been described in normal and Graves' thyroids; it contains exons 1-8 of the major mRNA species and a unique 3'-sequence predicted to encode further amino acids and a polyadenylated tail. Lacking the membrane-spanning region, the corresponding variant protein, if expressed, is not expected to couple to G-proteins. Using primers specific for this variant in reverse polymerase chain reaction experiments, Southern blotting and frequencies, we demonstrate the presence of this transcript in normal and Graves' thyroid, extraocular muscle, peripheral blood mononuclear cells, and, to a lesser extent, in fat and fibroblasts. TSH-mediated protein synthesis, cAMP, and glycosaminoglycan production have been measured in cultured fibroblasts. At 5 mU/mL, bovine TSH stimulated glycosaminoglycan production, but recombinant TSH did not, even at higher concentrations, suggesting that contaminating factors are responsible. Together the data do not support the presence of a functional complete TSHR in orbital tissue. However, they are compatible with a role for the extracellular portion of the receptor as a nonfunctional autoantigen and provide some explanation for the conflicting results with regard to the relevance of the TSHR in the pathophysiology of thyroid-associated ophthalmopathy.