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Identification of a Point Mutation in the Folate Receptor Gene That Confers a Dominant Negative Phenotype¹

Department of Pediatrics and Pharmacology, University of Texas Southwestern Medical Center at Dallas, 5323 Harry Hines Boulevard, Dallas, Texas 75235-9063

UM-SCC-38 cells, a squamous cell carcinoma cell line of the head and neck, express limited amounts of folate receptor antigen which is not capable of binding either folic acid or 5-methyltetrahydrofolic acid. Three distinct mutations in the open reading frame of the folate receptor were identified. We now show that the three mutants are nonfunctional with respect to folic acid binding because the protein products do not bind folate. Additionally, a study of MA104 cells (a receptor-positive cell line) transfected with each mutant was done. Expression of one mutant, FR-67, results in a dominant negative phenotype because folate binding is significantly reduced although membrane antigen is significantly increased. Coexpression of FR-67 and the normal protein in MA104 cells also results in large, bright clusters of receptor protein inside the cell around the nucleus when visualized using indirect immunofluorescence. These clusters are not found in cells that express either normal or FR-67 protein alone. In conclusion, this study provides the first evidence of a mutant folate receptor protein capable of affecting normal receptor function in a dominant negative manner.

¹ This work was supported by the American Cancer Society (grant #DHP681) and the Carl B. and Florence E. King Foundation. B. A. K. is an American Cancer Society Clinical Research Professor.

² To whom requests for reprints should be addressed, at University of Texas Southwestern Medical Center at Dallas, Department of Pediatrics and Pharmacology, Dallas, TX 75235-9063.

Received 8/ 5/94. Accepted 12/13/94.

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