Vol. 187, No. 2, 1992 September 16, 1992 BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS Pages 1135-1143 CLONING AND SEQUENCING OF A 1.3 KB VARIANT OF HUMAN THYROTROPIN RECEPTOR mRNA LACKING THE TRANSMEMBRANE DOMAIN Peter N. Graves,*Yaron Tomer and Terry F. Davies Division of Endocrinology and Metabolism, Department of Medicine, Mount Sinai School of Medicine, New York, New York Received August 12, 1992 We amplified human thyroidal cDNA using oligonucleotide primers designed to reveal putative human thyrotropin receptor (hTSHR) mRNA variants encoding the extracellu- lar, ligand-binding domain but lacking the transmembrane domain. Whereas the major 4.3 kb hTSHR mRNA species was not amplified to detectable levels, several shorter products were detected. A strongly amplified 1 kb product was cloned and sequenced. It contained coding sequences at the 5’ end which were colinear with exons l-8 of the hTSHR gene, encoding most of the extracellular domain. This was followed at the 3’ end by additional coding and noncoding information not present in the 4.3 kb transcript. A probe specific for the 5’ end recognized polyadenylated thyroidal transcripts of 4.3, 1.7, and 1.3 kb, indicating the presence of several hTSHR mRNA variants. A probe specific for the 3’ end recognized only the 1.3 kb transcript. The level of the 1.3 kb variant (hTSHR-VI.3 mRNA) was about half that of the 4.3 kb hTSHR mRNA and twice that of the 1.7 kb variant. The presence of a thyroidal mRNA encoding both the signal peptide and ligand-binding region of the hTSHR, but not the seven transmembrane helices, provides the potential to produce soluble receptors which could play important roles in thyroid physiology and/or autoimmune thyroid disease. 0 1992 Academic FTes5, Inc. A fundamental advance in the field of thyroid physiology has been the cloning and sequencing of the thyroid stimulating hormone receptor (TSHR) (I-5) (for review see (6)). While the role of TSH in positively regulating multiple thyroid functions has long been appreciated, knowledge of the TSH receptor structure makes possible the detailed molecular mechanisms of this trophic influence. The TSHR gene closely resembles that of other glycoprotein hormone receptors (FSHR, LHR, ADHR), which together define a new subfamily (subgroup B) of G protein-linked receptors. While all members of the superfamily contain seven membrane-spanning helical segments, the glycoprotein hormone receptors are distinguished by a large extracellular domain ‘To whom correspondence should be addressed at Box 1055, Mount Sinai Medical Center, 1 Gustave L. Levy Place, New York, NY 10029. 0006-291 Xi92 $4.00 Copwight 0 1992 by Academic Press, Inc. 1135 All rights of reproduction in any form reserved.