SignificanceThe nine-member transglutaminase protein family includes five known autoantigens. Because of the frequent roles of transglutaminases in autoimmunity, we decided to explore whether the remaining members might also constitute autoantigens, but in as-yet-unexplained disorders. We turned to TGM1, and since this member is primarily expressed in squamous epithelia, we focused on skin disorders. By screening a broad range of acquired skin disorders, we identified TGM1 to be a major autoantigen in the severe blistering disease paraneoplastic pemphigus. This study illustrates a gene-centric approach to biomarker discovery—starting from a putative autoantigen to search for its corresponding disease—that may prove generally applicable for studies of autoimmunity.